JP2009504697A - Novel triazole derivatives as ghrelin analog ligands of growth hormone secretagogue receptors - Google Patents

Abstract

  The present invention is a novel triazole derivative as a ghrelin analog ligand of the growth hormone secretagogue receptor of formula (I), which is physiologically mediated in mammals, preferably humans, mediated by the GHS receptor. And / or triazole derivatives useful in the treatment or prevention of pathophysiological conditions. Furthermore, the present invention provides GHS receptor antagonists and agonists that can be used for the modulation of these receptors, which are suitable for the aforementioned conditions, especially “growth retardation, cachexia, short periods of energy balance, medium Long-term and / or long-term regulation; short-, medium- and / or long-term regulation of eating behavior (stimulation and / or inhibition); adipogenesis, adiposity and / or obesity; weight gain and / or decline Useful for treating "diabetes, type 1 diabetes, type 2 diabetes, tumor cell proliferation; inflammation, inflammatory effects, postoperative ileus of the stomach, postoperative ileus and / or gastrectomy (ghrelin replacement therapy)".

Description

  The present invention relates to novel triazole derivatives that act as ghrelin analog ligands of growth hormone secretagogue receptors. These compounds are useful in altering growth hormone plasma levels in mammals and in various physiological and pathophysiological conditions such as growth retardation, obesity, feeding behavior, energy balance, tumor cell proliferation, wound / burning Useful in the treatment and / or regulation of healing, metabolic diseases and inflammation.

Prior Art Ghrelin, a 28 amino acid peptide with a single octanoyl modification at Ser-3 (Kojima M et al. Nature 1999, 402: 656-660) is a growth hormone secretagogue receptor type 1a (GHS-R) 1a), identified as an endogenous ligand for G protein-coupled receptors (Howard AD et al. Science 1996, 273: 974-977). Ghrelin is mainly produced in the upper intestine / stomach, but small amounts were also detected in the intestine, pancreas, kidney, immune system, placenta, testis, pituitary, lung, and hypothalamus (van der Lely AJ et al. Endocrine Rev. 2004, 25: 426-457; Cowley M et al., Neuron 2003, 37: 649-661).

  In humans, ghrelin stimulates growth hormone (GH) through synergism with GHRH in GH secretion via a pathway independent of the GHRH receptor (Arbat E et al., J. Clin. Endocrinol. Metab. 2001, 86: 1169-1174). Furthermore, ghrelin also stimulates the secretion of ACTH, prolactin, cortisol, aldosterone and epinephrine (Arbat E et al. J. Clin. Endocrinol. Metab. 2001, 86: 1169-1174; Nagaya N et al. Am. J. Physiol.Regul.Integrr.Comp.Physiol.2001,280: R1483-1487; Takaya K et al., J.Clin.Endocrinol.Metab.2000, 85: 4908-4911).

  Since ghrelin was thought to be involved in metabolic regulation and energy expenditure, ghrelin expression and secretion of ghrelin from the stomach into the general circulation are expected to be affected by metabolic hormones. In obese humans, plasma ghrelin levels are reduced, suggesting that elevated insulin or leptin levels in obese subjects reduce ghrelin secretion (Tschop M et al. Diabetes 2001, 50: 707-709).

  Growth hormone release in humans and animals treats physiological or pathophysiological conditions characterized by a deficiency in growth hormone secretion and also treats these conditions that are ameliorated by growth hormone anabolism. It has been.

  Initially, the clinical application of GH was limited to the treatment of children with GH deficiency, but the commercialization of recombinant human growth factor (rhGH) has led to many studies supporting other potential clinical uses of GH. (Strobl JS et al., Pharmacol. Rev. 1994, 46: 1-34; Torosian MH, J. Pediatr. Endocrinol. 1993, 6: 93-97). rhGH has shown promise in the treatment of patients with burns, wounds and fractures, and more recently has shown promise in body composition changes, as well as glucocorticoid reversion, chemotherapy and AIDS (Rudman). D. et al., N. Engl. J. Med. 1990, 323: 1-6; Papadakis MA et al., Ann. Inter. Med. 1996, 124: 708-716, Welle S et al., J. Clin. Endocrinol. Metab. 1996, 81: 3239-3243).

  GH synthesized and stored in the pituitary gland is released under the control of two known hypothalamic hormones: growth hormone releasing hormone (GHRH) and the inhibitory hormone somatostatin (SRIF). In most cases, GH deficiency is associated with hypothalamic defects and not GH pituitary deficiency. Thus, as an alternative treatment for rhGH, GH deficient patients could also be treated with any compound that releases endogenous GH from the pituitary gland. This can be done using GHRH which stimulates GH release, but can also be done using synthetic growth hormone secretagogues.

  A number of synthetic, peptidic and non-peptidic GHSs, such as GHRPs 1, 2 and 6, hexarelin, MK-0677, EP-01572 are among the receptors that were not identified at that time "GHS receptors". Some of them have been shown to bind specifically long before the discovery of ghrelin receptor and ghrelin / GHS receptor (for further reference, see Frontier of Camni F et al. Neuroendocrinol. 1998, 19: 47-72 ";" Casa-nueva FF et al., Trends Endocrinol. Metab. 1999, 10: 30-38 ";" van der Lely AJ et al., Endocrine Rev. 2004, 25: 25. 457 ") GHS also exhibits a strong GH-releasing action. And has the same biological activity as described above for ghrelin.

  GHS is also disclosed in the following patents or patent applications (not an exhaustive list): US 6,071,926, US 6,329,342, US 6,194,578, US 2001/0041673. No., US 6,251,902, US 2001/0020012, US 2002/0013320, US 2002/0002137, WO 95/14666, WO 96/15148, WO 01/96300.

  While ghrelin / GHS-induced GH secretion is mediated by activation of ghrelin / GHS receptor type 1a (GHS-R 1a), so far at least some of the other actions of ghrelin and GHS Are supported by different receptors of the GHS receptor family or even at different binding sites of a given GHS receptor.

  GHS receptors are concentrated in the hypothalamic-pituitary region, but are also likely to be distributed in other central and peripheral tissues (Hattori N et al., J. Clin. Endocrinol. Metab. 2001). 86: 4284-4291; Ganapavan S et al., J. Clin. Endocrinol. Metab. 2002, 87: 2988-2991; Muccolii G et al., J. Endocrinol. 2000, 157: 99-106; Endocrinol.2000, 61: 27-31; Muccioli G et al., Eur.J.Pharmacol.2002,440: 235-254; Papotti M et al., J.Clin.Endocrinol.Metab.2000. 85: 3803-3807; Cassoni P et al., J. Clin. Endocrinol. Metab. 2001, 86: 1738-1745; Guan XM et al., Brain Res. MoI. Brain Res. 1997, 48: 23-29; Pajot MT et al., Endocrine 2001, 14: 1-8; Korbonits M et al., J. Clin. Endocrinol. Metab. 1998, 83: 3624-3630).

  Two types of GHS type 1 receptors, GHS-R 1a and GHS-R 1b, have been identified, which in humans are probably expressed by a single gene and are alternatively spliced (van der Lely AJ et al. Endocrine Rev. 2004, 25: 426-457; Howard AD et al. Science 1996, 273: 974-977; Smith RG et al. Endocr. Rev. 1997, 18: 621-645; Smith RG et al., Endocrine 2001 14: 9-14; McKee KK et al., Mol. Endocrinol. 1997, 11: 415-423; Petersen S, Minerva Endocrinol. 2002; 27: 243-256). Among mammalian species, a high degree of sequence identity has been reported for GHS-R 1a (Petersen S, Minerva Endocrinol. 2002; 27: 243-256: 91.8% to 95.6%). .

  The motilin receptor was discovered as a member of the GHS receptor family with 52% identity (Smith RG et al., Endocrine 2001, 14: 9-14; McKee KK et al., Genomics 1997, 46: 426-434. ). Gastrointestinal motilin receptor 1a and GHS-R 1a show high similarity (Smith RG et al. Endocrine 2001, 14: 9-14; Feighner SD et al. Science 1999, 284: 2184-2188).

  Members of other GHS receptor families appear to be the neurotensin receptor, TRH receptor, GPR38 (FM1), GPR39 (FM2) and FM3 (Smith RG et al. Endocr. Rev. 1997, 18: 621). Smith RG et al., Horm.Res. 1999, 51 (Suppl. 3): 1-8; Tan CP et al., Genomics 1998, 52: 223-229; Howard AD et al., Science 1996, 273: 974. -977). Additional GHS receptor subtypes appear to exist in a wide variety of central and peripheral tissues (van der Lely AJ et al., Endocrine Rev. 2004, 25: 426-457). For example, cardiac GHS-R having a putative sequence similar to that of CD36, a multifunctional receptor known as glycoprotein IV, has been reported (Boartt V et al., Circ. Res. 1999, 85: 796-). 802). Cassoni et al. (J. Clin. Endocrinol. Metab. 2001, 86: 1738-1745) are neoplastic breast cells activated by ligand binding to a specific binding site different from the classical GHS-R type 1. Reported the existence of a subtype of GHS-R. Furthermore, the data collected by these authors supports the hypothesis that even different binding site subtypes exist for GHS-R in peripheral organs, which are probably due to their endocrine or non-endocrine. But also due to their normal or neoplastic nature.

  The ubiquitous nature of GHS binding sites explains that ghrelin and synthetic GHS are involved in several important physiological and pathophysiological conditions, regardless of their strong growth hormone secretagogue properties. is doing.

  Thus, potential clinical applications include, among others, the following a) -h).

a) Short, medium and long term regulation of energy balance and / or feeding behavior (Tschop M et al. Nature 2000, 407: 908-913; Asaka A et al. Gut 2003, 52: 947-952; US 2001/0020012; Kojima M et al., Curr. Opin. Pharmacol. 2002, 2: 665-668; Horvath TL et al., Curr. Pharm. Des. 2003, 9: 1383-1395; Clin. Endocrinol. Metab. 2001, 86: 5992-5995)
The expression of GHS-R1a is shown in neurons in the paraventricular nucleus of the hypothalamus. These neurons send output to the main hypothalamic circuit for control of feeding behavior, such as the arcuate nucleus that produces the mediator NPY. Stimulation of feeding behavior by ghrelin and / or GHS is thought to be mediated by an increase in NPY in the arcuate nucleus (Willesen MG et al., Neuroendocrin. 1999, 70: 306-316). Single administration of anti-ghrelin IgG (intraventricular or intraperitoneal) suppressed rapid feeding in lean rats (Bagnasco M et al. Regul. Pept. 2003, 111: 161-167). Intraventricular administration of anti-ghrelin IgG twice a day reduced body weight over a period of 5 days (Murakami N et al., J. Endocrinol. 2002, 174: 283-288).

  A recent study using the peptide GHS-R 1a antagonist [D-Lys-3] -GHRP-6 supports feeding behavior and weight loss in diet-induced obese mice (Asakawa A et al. Author Gut, 2003, 52: 947-952). The fact that peptidic compounds, initially characterized as growth hormone secretagogues, can selectively stimulate the feeding behavior of rats without induction of growth hormone secretion is the result of GHS- in the hypothalamus. This suggests the existence of a GHS-R subtype different from R1a (Torsello A et al., Neuroendocrin. 2000, 72: 327-332; Torsello A et al., Eur. J. Pharmacol. 1998, 360: 123-129. ).

b) Treatment of adipogenesis, adiposity and / or obesity and weight loss (Tschop M et al. Nature 2000, 407: 908-913; Asaka A et al. Gut 2003. 52: 947-952)
Long-term administration of ghrelin and / or GHS in freely fed mice and rats causes weight gain and reduced fat utilization (Tschop M et al., Nature 2000, 407: 908-913). In addition, ghrelin and des-octanoyl ghrelin promote adipogenesis in vivo (Thompson NM et al., Endocrinol. 2004, 145: 234-242), and promote isoproterenol-induced lipolysis in rat adipocytes. It has been reported to inhibit via non-R 1a forms (Muccioli G et al., Eur. J. Pharmacol. 2004, 498: 27-35). On the other hand, there is also a report describing that the expression of GHS-R1a in rat adipocytes increases with age and during adipogenesis (Choi K et al., Endocrinol. 2003, 144, 754-759). ).

c) Treatment of tumor cell proliferation As in the case of other members of the hypothalamic-pituitary axis that regulate growth hormone secretion, ghrelin and GHS receptors are important autocrine / parasites in some cancers. Evidence appears to play a secretory role (Jeffery PL et al., Cytokine Growth Factor Rev. 2003, 14: 113-122). Specific binding sites for ghrelin, peptidic and non-peptidic GHS can be found in tumor tissues such as prostate cancer cell line PC3 (Jeffery PL et al., J. Endocrinology 2002, 172: R7-R11), thyroid tissue (Cassoni P. et al., J. Endocrinol. 2000, 165: 139-146) and lung cancer cells CALU-1 (Ghe C et al., J. Clin. Endocrinol. Metab. 2001, 86: 1738-1745).

  In the case of the breast, specific binding sites for GHS were found in the tumor tissue, but normal breast parenchyma does not have such a receptor. Synthetic GHS is found in the proliferation of lung cancer cells CALU-1 (Ghe C et al., Endocrinol. 2002, 143: 484-491) and breast cancer cell lines (Cassoni P et al., J. Clin. Endocrinol. Metab. 2001, 86. : 1738-1745).

  Both ghrelin and non-acylated ghrelin bind to tumor tissue. Since non-acylated ghrelin cannot bind GHS-R1a, the binding site of GHS to tumor tissue appears to be different from GHS-R1a. From these data, on the one hand, the binding site in the tumor tissue is expected to recognize the ligand of GHS-R1a, and on the other hand it is expected to recognize a chemical structure that has not yet been characterized. Synthetic ligands for GHS-R1a thus have the ability to inhibit the growth of tumor cells that express a subtype of the GHS receptor.

d) Treatment of inflammation / inflammatory action Anti-inflammatory action of ghrelin agonist growth hormone releasing peptide-2 (GHRP-2) in chronic arthritis with hypermetabolism and clinical manifestations of cachexia has been demonstrated (Granado M et al. Am. J. Physiol. Endocrinol. Metab. 2005, 288: E486-492). These data suggest that the anti-inflammatory effect of GHRP-2 is mediated by activation of the ghrelin receptor expressed by immunocompetent cells.

e) Treatment of cachexia Supporting the anti-cachectic effect of administered recombinant growth hormone in an animal model of cachexia (Roubenoff R et al., Arthritis Rheum. 1997, 40 (3): 534-539) (Ibanez de Caceres I et al., J. Endocrin. 2000, 165 (3): 537-544). That finding is also promising in data from patients with rheumatoid arthritis (Rubenoff R et al., J Clin Invest. 1994, 93 (6): 2379-2386).

f) Gastrectomy treatment (ghrelin replacement therapy)
Ghrelin, a stomach hormone, was administered to mice and subjected to gastrectomy or sham surgery (Donnonville de la Cour et al., Gut 2005, 54 (7): 907-913). The results shown confirm that ghrelin replacement therapy at least partially reverses weight loss and body fat loss induced by gastrectomy.

g) Treatment of postoperative ileus (gastric) The effect of ghrelin on the motor function of the gastrointestinal tract of rats was evaluated. It could be proved that ghrelin reverses the delay in gastric emptying and is a potent gastric motility agent useful for the treatment / reversion of gastric postoperative ileus (Trudel L et al. Am J Physiol Gastrointest Liver Physiol 2002, 282 (6): G948-G952).

h) Treatment of diabetes (type 1 diabetes and type 2 diabetes) The depleting effect of ghrelin in leptin-deficient mice was studied (Sun et al. Cell Metabolism 2006, 3: 379-386). The results show that ghrelin deficiency increases insulin secretion in response to glucose load, indicating that inhibition of ghrelin or neutralizing its activity includes both type 1 and type 2 diabetes (See also WO 03/051389).

  Further areas of application are accelerated recovery of patients undergoing major surgery (eg US 6,194,578); accelerated recovery of burn patients (eg US 6,194,578); protein catabolic response after major surgery Attenuation of cachexia and protein deficiency due to acute or chronic illness (eg US 6,194,578); in patients who have received medical treatment in combination with antidepressants Treatment of central nervous system diseases (eg US 2002/0002137 A1); Fracture repair and promotion of cartilage growth (eg US 6,194,578); Osteoporosis treatment or prevention; Immune system stimulation; Wound healing promotion (eg US 6 194, 578); treatment of growth retardation associated with Prader-Willi syndrome, Turner syndrome and obesity; intrauterine growth retardation, skeletal dysplasia, Treatment of hypercortical function and Cushing syndrome; treatment of osteochondrosplasia, Noonan syndrome, schizophrenia, depression and Alzheimer's disease; treatment of pulmonary dysfunction and ventilation dependence; hyperinsulinemia including islet cell disease Treatment; adjuvant treatment for ovulation induction; suppression of age-related decline in thymic function; improvement of muscle strength and motility (eg US 6,194,578); maintenance of skin thickness (eg US 6,194,578) Improved sleep quality (eg, US Pat. No. 6,071,926); congestive heart failure alone (eg, US Pat. No. 6,329,342; US Pat. No. 6,194,578), in combination with a corticotropin releasing factor antagonist (eg, US 2001) / 0041673); metabolic homeostasis or renal homeostasis (eg in frail elderly people) ( For example US 6,194,578); improved glycemic control (eg US 6,251,902); treatment of systemic lupus erythematosus and inflammatory bowel disease (eg US 2002/0013320); treatment of weakness associated with age or obesity Or prevention (eg US 6,194,578); as well as osteoblast stimulation.

  Animals have potential applications such as stimulation of feeding behavior (Wren AM et al., Diabetes 2001, 50: 2540-2547), stimulation of the immune system and treatment of aging diseases in domestic animals, promotion of livestock growth and sheep. Is not ignored in stimulating wool growth in

  Compounds containing a triazole moiety are widely recognized in medicinal chemistry because of their various biological activities. The following patent families all relate to heterocyclic compounds that are believed to exhibit certain biological effects for use in various pharmaceutical indications. The triazole moiety is potentially or explicitly included. However, none of these patent families mentions ghrelin analog ligands of the GHS receptor family, nor does it describe the modulation of these receptors, nor does it mention GH secretagogue properties.

  WO 2004/11115 discloses glucocorticoid receptor modulators. WO 2004/052280 describes anti-angiogenic compounds as inhibitors of VEGF receptor tyrosine kinase activity and their use in cancer. WO 2004/096795 also discloses tyrosine kinase inhibitors, preferably C-FMS inhibitors. Both WO03 / 011831 and WO03 / 011210 describe heteroarylheteroalkylamine derivatives as inhibitors of nitric oxide synthase. WO 02/00651 relates to a factor XA inhibitor for use in thromboembolic diseases. Both WO01 / 94318 and WO01 / 94317 describe chemical libraries of substituted azole derivatives and their synthetic methods for use in high-throughput drug discovery screening. However, they do not provide any biological activity or any medical use, nor do they name specific compounds. Both WO 00/76971 and WO 00/76970 claim serine protease inhibitors that are effective as antithrombotic agents. WO 01/36395 discloses triazole derivatives as farnesyl transferase inhibitors. WO 96/33176 and US 5,703,092 relate to hydroxamic acid compounds as metalloproteases and TNF inhibitors. WO 93/09095 describes 2-heterocyclic ethylamine derivatives and their use in neurological and neurodegenerative diseases. WO 2004/103270 claims compounds for the treatment of thrombosis, in particular factor XIa inhibitors. WO 98/38177, US 6,506,782, US 6,849,650 and US 2003/0130188 are all heterocyclic compounds for use in Alzheimer's disease as inhibitors of β-amyloid peptide release or synthesis Is described.

  Heterocyclic compounds that can be useful as GHS are also described in the literature.

  WO 00/54729 discloses, for example, heterocyclic aromatic compounds as GH secretagogues, which are believed to stimulate endogenous production and / or release of GH, and the triazole moiety May be included. Further described is a method of administering such GHS to increase the level of endogenous GH or to increase the endogenous production or release of GH. Furthermore, the administration or administration of such GHS prevents or treats osteoporosis (improves bone density and / or bone strength) or treats obesity, or increases muscle mass and / or increases muscle strength and muscle function in elderly humans, or Methods are provided for reversing or preventing faintness in elderly people.

  However, while claiming GH release in vivo, WO 00/54729 has practically failed to verify such effects. Neither in vitro nor in vivo data has been included that demonstrate any stimulation of GH or any increase in endogenous production and / or release of GH.

  Furthermore, WO 00/54729 fails to describe and demonstrate the action of the claimed compounds on some biological target. That is, the claimed compounds have not been shown or described as ligands of one or more specific receptors, for example the receptor family that binds to them and alters their activity.

  Furthermore, WO 00/54729 fails to demonstrate and describe the inhibitory and / or antagonist activity of the claimed compounds. In fact, such compounds have not been shown to reduce endogenous GH levels and / or inhibit or reduce endogenous production and / or release of GH. The inhibitory effect on any of the receptors mentioned has also not been revealed.

  US 6,525,203, US 6,518,292, US 6,660,760 are members of the same patent family as WO 00/54729, but no longer contain a triazole moiety as the claimed subject matter. With respect to biological activity, the same applies as described above for WO 00/54729.

  WO 2004/021984 describes heterocyclic aromatic GH secretagogues, which are believed to be effective in stimulating the endogenous production or release of GH. However, the claimed compounds consist of bicyclic to tetracyclic aromatic rings and do not contain triazoles.

  Similar to WO 00/54729, GH release in vivo is claimed, but neither in vitro nor in vivo data supports any stimulation of GH or an increase in endogenous production and / or release of GH. Not included. With respect to biological activity, the same applies as described above for WO 00/54729.

  WO 97/23508 claims peptidomimetic compounds as GHS, which act directly on pituitary cells in vitro to release GH therefrom and improved properties, For example, improved resistance to proteolysis and improved biocompatibility. Furthermore, the claimed compounds could also be administered in vivo to enhance GH release. These compounds are peptide derivatives and do not clearly contain a triazole moiety.

  However, once again, as in WO 00/54729 and WO 2004/021984, WO 97/23508 also describes in vitro data that supports the claimed effect or in vivo data, eg, direct to pituitary cells. It has failed to show action, GH release therefrom and improved properties. Furthermore, with regard to biological activity and inhibitory / antagonist activity, the same applies as described above for WO 00/54729.

  US 6,127,391, US 5,977,178 and US 6,555,570 are members of the same patent family as WO 97/23508. The same facts as indicated for WO 97/23508 apply.

DESCRIPTION OF THE INVENTION The object of the present invention was to provide novel compounds which can be used for the treatment of physiological and / or pathophysiological conditions mediated by GHS receptors in mammals, in particular humans. It was. Another object of the present invention is to provide a compound for said treatment which is achieved by alteration of the GHS receptor. A further object of the present invention is to provide antagonists of GHS receptors for these treatments. Yet another object of the present invention is to provide antagonists of GHS receptors for these treatments.

［式中：
Ｒ１及びＲ２は、互いに無関係に、"水素原子、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル"からなる群から選択され、それらは、場合により、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル及び／又はヘテロシクリルアルキル基において、"ハロゲン、−Ｆ、−Ｃｌ、−Ｂｒ、−Ｉ、−Ｎ₃、−ＣＮ、−ＮＲ７Ｒ８、−ＯＨ、−ＮＯ₂、アルキル、アリール、アリールアルキル、−Ｏ−アルキル、−Ｏ−アリール、−Ｏ−アリールアルキル"からなる群から無関係に選択される３個までの置換基によって置換されており、有利には、"アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル"からなる群から選択され、それらは、場合により、"ハロゲン、−Ｆ、−Ｃｌ、−Ｂｒ、−Ｉ、−Ｎ₃、−ＣＮ、−ＮＲ７Ｒ８、−ＯＨ、−ＮＯ₂、アルキル、アリール、アリールアルキル、−Ｏ−アルキル、−Ｏ−アリール、−Ｏ−アリールアルキル"からなる群から無関係に選択される３個までの置換基によって置換されており；
基Ｒ３とＲ４の一方は、水素原子であるが、他方の基は、"水素原子、アルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、−アルキル−Ｏ−アリール、−アルキル−Ｏ−アリールアルキル、−アルキル−Ｏ−ヘテロアリール、−アルキル−Ｏ−ヘテロアリールアルキル、−アルキル−Ｏ−ヘテロシクリル、アルキル−Ｏ−ヘテロシクリルアルキル、−アルキル−ＣＯ−アリール、−アルキル−ＣＯ−アリールアルキル、−アルキル−ＣＯ−ヘテロアリール、−アルキル−ＣＯ−ヘテロアリールアルキル、−アルキル−ＣＯ−ヘテロシクリル、−アルキル−ＣＯ−ヘテロシクリルアルキル、−アルキル−Ｃ（Ｏ）Ｏ−アリール、−アルキル−Ｃ（Ｏ）Ｏ−アリールアルキル、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロアリール、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロアリールアルキル、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロシクリル、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロシクリルアルキル、−アルキル−ＣＯ−ＮＨ₂、−アルキル−ＣＯ−ＯＨ、−アルキル−ＮＨ₂、−アルキル−ＮＨ−Ｃ（ＮＨ）−ＮＨ₂、アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル、アルキル−Ｓ−アルキル、アルキル−Ｓ−Ｈ"からなる群から選択され、それらは、場合により、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル及び／又はヘテロシクリルアルキル基において、"ハロゲン、−Ｆ、−Ｃｌ、−Ｂｒ、−Ｉ、−Ｎ₃、−ＣＮ、−ＮＲ７Ｒ８、−ＯＨ、−ＮＯ₂、アルキル、アリール、アリールアルキル、−Ｏ−アルキル、−Ｏ−アリール、−Ｏ−アリールアルキル"からなる群から無関係に選択される３個までの置換基によって置換されており、有利には"アリールアルキル、ヘテロアリールアルキル、ヘテロシクリルアルキル、−アルキル−Ｏ−アリール、−アルキル−Ｏ−アリールアルキル、−アルキル−Ｏ−ヘテロアリール、−アルキル−Ｏ−ヘテロアリールアルキル、−アルキル−Ｏ−ヘテロシクリル、アルキル−Ｏ−ヘテロシクリルアルキル、−アルキル−ＣＯ−アリール、−アルキル−ＣＯ−アリールアルキル、−アルキル−ＣＯ−ヘテロアリール、−アルキル−ＣＯ−ヘテロアリールアルキル、−アルキル−ＣＯ−ヘテロシクリル、アルキル−ＣＯ−ヘテロシクリルアルキル、−アルキル−Ｃ（Ｏ）Ｏ−アリール、−アルキル−Ｃ（Ｏ）Ｏ−アリールアルキル、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロアリール、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロアリールアルキル、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロシクリル、−アルキル−Ｃ（Ｏ）Ｏ−ヘテロシクリルアルキル、−アルキル−ＣＯ−ＮＨ₂、−アルキル−ＣＯ−ＯＨ、−アルキル−ＮＨ₂、−アルキル−ＮＨ−Ｃ（ＮＨ）−ＮＨ₂"からなる群から選択され、それらは、場合により、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル及び／又はヘテロシクリルアルキル基において、"ハロゲン、−Ｆ、−Ｃｌ、−Ｂｒ、−Ｉ、−Ｎ₃、−ＣＮ、−ＮＲ７Ｒ８、−ＯＨ、−ＮＯ₂、アルキル、アリール、アリールアルキル、−Ｏ−アルキル、−Ｏ−アリール、−Ｏ−アリールアルキル"からなる群から無関係に選択される３個までの置換基によって置換されており；
Ｒ５は、"水素原子、アルキル、シクロアルキル、シクロアルキルアルキル、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、−ＣＯ−アルキル、−ＣＯ−シクロアルキル、−ＣＯ−シクロアルキルアルキル、−ＣＯ−アリール、−ＣＯ−アリールアルキル、−ＣＯ−ヘテロアリール、−ＣＯ−ヘテロアリールアルキル、−ＣＯ−ヘテロシクリル、−ＣＯ−ヘテロシクリルアルキル、−ＣＯ−Ｃ^*（Ｒ９Ｒ１０）−ＮＨ₂、−ＣＯ−ＣＨ₂−Ｃ^*（Ｒ９Ｒ１０）−ＮＨ₂、−ＣＯ−Ｃ^*（Ｒ９Ｒ１０）−ＣＨ₂−ＮＨ₂、アルキルスルホニル、アリールスルホニル、アリールアルキルスルホニル"からなる群から選択され、それらは、場合により"ハロゲン、−Ｆ、−Ｃｌ、−Ｂｒ、−Ｉ、−Ｎ₃、−ＣＮ、−ＮＲ７Ｒ８、−ＯＨ、−ＮＯ₂、アルキル、アリール、アリールアルキル、−Ｏ−アルキル、−Ｏ−アリール、−Ｏ−アリールアルキル"からなる群から無関係に選択される３個までの置換基によって置換されており、有利には、"水素原子、−ＣＯ−アルキル、−ＣＯ−シクロアルキル、−ＣＯ−アリール、−ＣＯ−ヘテロアリール、−ＣＯ−アリールアルキル、−ＣＯ−ヘテロアリールアルキル、−ＣＯ−ヘテロシクリル、−ＣＯ−Ｃ^*（Ｒ９Ｒ１０）−ＮＨ₂、−ＣＯ−ＣＨ₂−Ｃ^*（Ｒ９Ｒ１０）−ＮＨ₂、−ＣＯ−Ｃ^*（Ｒ９Ｒ１０）−ＣＨ₂−ＮＨ₂"からなる群から選択され、それらは、場合により、"ハロゲン、−Ｆ、−Ｃｌ、−Ｂｒ、−Ｉ、−Ｎ₃、−ＣＮ、−ＮＲ７Ｒ８、−ＯＨ、−ＮＯ₂、アルキル、アリール、アリールアルキル、−Ｏ−アルキル、−Ｏ−アリール、−Ｏ−アリールアルキル"からなる群から無関係に選択される３個までの置換基によって置換されており；
Ｒ６は、"水素原子、アルキル、シクロアルキル、シクロアルキルアルキル"からなる群から選択され、有利には水素原子であり；
Ｒ７及びＲ８は、互いに無関係に、"水素原子、アルキル、シクロアルキル、シクロアルキルアルキル"からなる群から選択され、有利には水素原子であり；
Ｒ９及びＲ１０は、互いに無関係に、"水素原子、アルキル、中性のα−アミノ酸側鎖、非中性のα−アミノ酸側鎖"からなる群から選択され、有利には、"水素原子、アルキル"からなる群から選択され；
ｍは、０、１又は２であり、有利には０であり；かつ
^*は、キラルである場合に、Ｒ立体配置もしくはＳ立体配置の炭素原子を意味する］で示される化合物であって、ＧＨＳ受容体によって媒介される哺乳動物における生理学的な及び／又は病態生理学的な状態の治療又は予防のための医薬品の製造のために使用することができる化合物を提供することによって解決された。 The subject of the present invention is, surprisingly, in one aspect, a compound of formula (I)

[Where:
R1 and R2 are independently of each other “a hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, aryl. Selected from the group consisting of "alkylsulfonyl", which is optionally alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups with "halogen,- F, -Cl, -Br, -I, -N 3, -CN, -NR7R8, -OH, -NO 2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl , -O-arylalkyl "substituted by up to three substituents independently selected from the group consisting of" alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl " Are optionally selected from “halogen, —F, —Cl, —Br, —I, —N ₃ , —CN, —NR 7 R 8, —OH, —NO ₂ , alkyl, aryl, arylalkyl, — Substituted with up to three substituents independently selected from the group consisting of “O-alkyl, —O-aryl, —O-arylalkyl”;
One of the groups R3 and R4 is a hydrogen atom, while the other group is "hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl,- Alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO- Arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, -alkyl-CO-heterocyclylalkyl, -alkyl-C (O) O-aryl, -alkyl-C (O) O-Aryl A Alkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O-heterocyclyl, -alkyl-C (O) O-heterocyclylalkyl, - alkyl -CO-NH _2, - alkyl -CO-OH, - alkyl -NH _2, - alkyl _{-NH-C (NH) -NH 2} , alkylsulfonyl, arylsulfonyl, aryl-alkylsulfonyl, alkyl -S- alkyl, Selected from the group consisting of “alkyl-S—H”, optionally in aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups, “halogen, —F, —Cl, — _{br, -I, -N 3, -CN} , -NR7R8, -OH, -NO 2, alkylenediamines , Aryl, arylalkyl, —O-alkyl, —O-aryl, —O-arylalkyl ”, preferably substituted with up to three substituents independently selected from the group consisting of“ arylalkyl, Heteroarylalkyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O- Heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl,- Alkyl-C (O O-aryl, -alkyl-C (O) O-arylalkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O- heterocyclyl, - alkyl -C (O) O-heterocyclylalkyl, - alkyl -CO-NH _2, - alkyl -CO-OH, - alkyl -NH _2, - consisting of alkyl _{-NH-C (NH) -NH 2} " Selected from the group, optionally in the aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups, “halogen, —F, —Cl, —Br, —I, —N ₃ , -CN, -NR7R8, -OH, -NO _2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl , -O-arylalkyl "substituted by up to 3 substituents independently selected from the group consisting of:
R5 represents “hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —CO-alkyl, —CO-cycloalkyl, —CO-cycloalkylalkyl. , -CO- aryl, -CO- arylalkyl, -CO- heteroaryl, -CO- heteroarylalkyl, -CO- heterocyclyl, -CO- ^{heterocyclylalkyl, -CO-C * (R9R10)} -NH 2, -CO —CH ₂ —C ^* (R 9 R 10) —NH ₂ , —CO—C ^* (R 9 R 10) —CH ₂ —NH ₂ , alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl ”, which are optionally "Halogen, -F, -Cl, _{Br, -I, -N 3, -CN} , -NR7R8, -OH, -NO 2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl, independently from the group consisting of -O- arylalkyl " Is preferably substituted by up to three substituents selected from: "hydrogen atom, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-aryl alkyl, -CO- heteroarylalkyl, -CO- ^{heterocyclyl, -CO-C * (R9R10)} -NH 2, -CO-CH 2 -C * (R9R10) -NH 2, -CO-C * (R9R10) - "is selected from the group consisting of, they can optionally," CH ₂ -NH ₂ halogen, -F, -Cl, -Br, -I , -N 3, -CN, -NR7R8, -OH, -NO 2 Alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl, which is substituted by up to three substituents selected independently from the group consisting of -O- arylalkyl ";
R6 is selected from the group consisting of "hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl", preferably a hydrogen atom;
R7 and R8, independently of one another, are selected from the group consisting of “hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl”, preferably a hydrogen atom;
R9 and R10 are independently selected from the group consisting of “hydrogen atom, alkyl, neutral α-amino acid side chain, non-neutral α-amino acid side chain”, preferably “hydrogen atom, alkyl Selected from the group consisting of;
m is 0, 1 or 2, preferably 0; and
^* Means a carbon atom in the R or S configuration when chiral, and is physiological and / or pathophysiological in mammals mediated by the GHS receptor. It has been solved by providing compounds that can be used for the manufacture of a medicament for the treatment or prevention of various conditions.

In a preferred embodiment, it is represented by the above formula (I),
R3 represents "-alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl, -Alkyl-C (O) O-aryl, -alkyl-C (O) O-arylalkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl -C (O) O-heterocyclyl, - alkyl -C (O) O-heterocyclylalkyl, - alkyl -CO-NH _2, - alkyl -CO-OH, - alkyl _{-NH-C (NH) -NH 2} , alkyl -S-alkyl, alkyl-SH ", preferably" -alkyl-CO-aryl " Kill, - alkyl -C (O) O-arylalkyl, - alkyl -CO-NH _2, - a compound selected from the group consisting of alkyl -CO-OH ", mammal mediated by GHS receptors Compounds are provided that can be used for the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in

In another preferred embodiment, it is represented by formula (I) above, wherein
R4 is a hydrogen atom;
R5 represents "hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, -CO-cycloalkyl,- Selected from the group consisting of "CO-cycloalkylalkyl, -CO-aryl, -CO-arylalkyl, -CO-heteroaryl, -CO-heteroarylalkyl, -CO-heterocyclyl, -CO-heterocyclylalkyl" However,
If R5 is "-CO-heteroarylalkyl" then "heteroaryl" is not an imidazole and R5 is "-CO-heterocyclyl" and "heterocyclyl" contains only nitrogen atoms as heteroatoms For example, if "heterocyclyl" contains at least two nitrogen atoms and R5 is "-CO-heterocyclylalkyl" and "heterocyclyl" contains only nitrogen atoms as heteroatoms, then "heterocyclyl" “When 1 or 2 nitrogen atoms are contained, the nitrogen atom is located at the 1-position of“ heterocyclyl ”which is an atom that directly bonds“ heterocyclyl ”and carbonyl group“ —CO— ”. Not located;
"Alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, -CO-cycloalkyl, -CO-cycloalkylalkyl, “—CO-aryl, —CO-reelalkyl, —CO-heteroaryl, —CO-heteroarylalkyl, —CO-heterocyclyl and / or —CO-heterocyclylalkyl” are sometimes referred to as “halogen, —F, —Cl _{, -Br, -I, -N 3,} -CN, -NR7R8, -OH, -NO 2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl, the group consisting of -O- arylalkyl " Selected independently from Substituted with up to 3 substituents provided that
When R5 is "-CO-cycloalkyl" or "-CO-cycloalkylalkyl", R5 is "cycloalkyl" and when R5 is "-CO-cycloalkyl", the carbonyl group "-CO- In the case where “and” or R5 is “—CO-cycloalkylalkyl”, the cycloalkyl, which is a carbon atom directly bonding to “alkyl”, is not substituted with NR7R8 at the 1-position, and R5 If "is" -CO-aryl "or" -CO-arylalkyl "and" aryl "is phenyl / benzene and is only substituted with one substituent, this one substitution The group is not -NR7R8;
R6 is a hydrogen atom;
R7 and R8, independently of one another, are selected from the group consisting of “hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl”, preferably a hydrogen atom; and m is 0, 1 or 2; A compound which is advantageously 0 and can be used for the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals mediated by GHS receptors. A compound is provided.

In a further aspect, the subject of the present invention is a compound of the formula (I) in which R 1 represents “hydrogen, methyl, (2-methoxyphenyl) -methyl, (3-methoxyphenyl) -methyl, (4-methoxy Phenyl) -methyl, (3-methoxyphenyl) -ethyl, (4-methoxyphenyl) -ethyl, phenyl, phenyl-methyl, phenyl-ethyl, (4-ethylphenyl) -methyl, (4-methylphenyl) -methyl , (4-fluorophenyl) -methyl, (4-bromophenyl) -methyl, (2,4-dimethoxyphenyl) -methyl, (3,5-dimethoxyphenyl) -methyl, 2,2-diphenyl-ethyl, naphthalene -1-yl-methyl, 1H-indol-3-yl-methyl, 2- (1H-indol-3-yl) -ethyl, 3- (1H-indole- 3-yl) -propyl, 4-methyl-phenyl, 4-ethyl-phenyl, n-hexyl, (3,4-dichlorophenyl) -methyl, (4-nitro-phenyl) -methyl, (pyridin-2-yl) -Methyl, (pyridin-3-yl) -methyl, (pyridin-4-yl) -methyl, (thiophen-2-yl) -methyl, (thiophen-3-yl) -methyl, (furan-2-yl) Selected from the group consisting of “methyl, (furan-3-yl) -methyl”;
R2 is “methyl, 1H-indol-3-yl-methyl, 2- (1H-indol-3-yl) -ethyl, 3- (1H-indol-3-yl) -propyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 2-methoxy-phenylmethyl, 3-methoxy-phenylmethyl, 4-methoxy-phenylmethyl, 2-methoxy-phenylethyl, 3-methoxy-phenylethyl, 4-methoxy -Selected from the group consisting of "phenylethyl";
R3 represents “hydrogen atom, methyl, propan-2-yl, 2-methyl-propan-1-yl, butan-2-yl, butan-1-yl, —CH ₂ —SH, — (CH ₂ ) ₂ —. S-CH _3, 1H-indol-3-yl - methyl, phenyl - methyl, 2-phenyl - ethyl, -CH ₂ -O-CH ₂ - phenyl, -CH ₂ -CO-CH ₂ - phenyl, - (CH _{2) 2} -CO-CH ₂ - phenyl, -CH ₂ -C (O) O- _{phenyl, - (CH 2) 2 -C} (O) O- phenyl, hydroxy - methyl, 1-hydroxy - ethane-1 _{yl, -CH 2 -CO-NH 2,} - (CH 2) 2 -CO-NH 2, (1- hydroxy - benzene-4-yl) - _{methyl, -CH 2 -CO-OH, -} (CH 2) _{2 -CO-OH, - (CH} 2) 4 -NH 2, (1H- imidazol-5 Yl) - _{methyl, - (CH 2) 3 -NH} -C (NH) -NH 2, - (CH 2) 3 -NH 2, - from (CH ₂₎ group consisting of ₃ -NH-CO-NH ₂ " Selected, preferably “1H-indol-3-yl-methyl, —CH ₂ —CO—CH ₂ -phenyl, — (CH ₂ ) ₂ —CO—CH ₂ -phenyl, —CH ₂ —C (O ) O-phenyl, — (CH ₂ ) ₂ —C (O) O-phenyl ”;
R4 is a hydrogen atom;
R5 is "hydrogen _{atom, -CO-CH 2 -NH 2 (} Gly _{residues), - CO-CH 2 -CH} 2 -NH 2 (β-Ala _{residue), - CO-CHCH 3 -NH} 2 (D -And / or L-α-Ala residue), -CO- (pyrrolidin-2-yl) (D- and / or L-Pro residue), 2-amino-2-carbonyl-propane (2-amino-) Isobutyric acid / Aib residue), 4-carbonyl-1H-piperidine, 3-carbonyl-1H-piperidine, R- (3-carbonyl-1H-piperidine), S- (3-carbonyl-1H-piperidine), 2- Carbonyl-1H-piperidine, R- (2-carbonyl-1H-piperidine), S- (2-carbonyl-1H-piperidine), 1-amino-2-carbonyl-benzene, carbonyl-cyclohexane, 2-acetyl-pyridy 3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine, 4-propionyl-pyridine, (R-1-amino) -2-carbonyl-cyclohexane, (S-1- Amino) -2-carbonyl-cyclohexane, 2-carbonyl-1H-imidazole, 2-carbonyl-pyridine, 3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-amino-3-carbonyl-pyridine, 2-carbonyl-pyrazine 2-carbonyl-4-hydroxy-1H-pyrrolidine, 4-carbonyl-1H, 3H-diazacyclohexane, methylsulfonyl, phenylsulfonyl, 1-carbonyl-1-amino-2-phenylethane, phenylmethyl, 1-carbonyl -4-azido-benzene, 2-carbo Nyl-2,5-dihydro-1H-pyrrole, 2-carbonyl-piperazine, 2-carbonyl-1H-pyrrolidine, 2-aminoethane, carbonyl-benzene, 2-carbonyl-pyrazine, 3-carbonyl-pyrazine, 4-carbonyl- Selected from the group consisting of "oxacyclohexane, 4-methyl-phenylsulfonyl, phenylmethyl-sulfonyl";
R6 is a hydrogen atom; and m is a compound of 0 for the treatment or prevention of a physiological and / or pathophysiological condition in a mammal mediated by a GHS receptor. It has been solved by providing compounds that can be used for manufacturing.

In a preferred embodiment, it is represented by the above formula (I),
R3 _{is, "- CH 2 -CO-CH} 2 - _{phenyl, - (CH 2) 2 -CO} -CH 2 - _{phenyl, -CH 2 -CO-NH 2,} - (CH 2) 2 -CO-NH 2, _{-CH 2 -CO-OH, - (} CH 2) 2 -CO-OH, - (CH 2) 3 -NH-C (NH) -NH 2, -CH 2 -SH, - (CH 2) 2 -S A compound selected from the group consisting of —CH ₃ ”for the manufacture of a medicament for the treatment or prevention of a physiological and / or pathophysiological condition in a mammal mediated by a GHS receptor Compounds are provided that can be used.

In another preferred embodiment, it is represented by formula (I) above, wherein
R5 is “hydrogen atom, methylsulfonyl, phenylsulfonyl, carbonyl-cyclohexane, (R-1-amino) -2-carbonyl-cyclohexane, (S-1-amino) -2-carbonyl-cyclohexane, 2-carbonyl-pyridine. 3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-acetyl-pyridine, 3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine, 4-propionyl-pyridine, 2 A compound selected from the group consisting of “amino-3-carbonyl-pyridine, 2-carbonyl-1H-imidazole, 2-carbonyl-pyrazine, 4-carbonyl-1H, 3H-diazacyclohexane”, and a GHS receptor Physiology in mammals mediated by And / or compounds which can be used for the production of a medicament for the treatment or prophylaxis of pathophysiological conditions is provided.

In a further aspect, the object of the present invention has been surprisingly solved by providing novel triazole compounds selected from the group of the following compounds 1-190:
Compound 1 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 2 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 3 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 4 (R) -N- (1- (5-benzyl-4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 5 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 6 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 7 (R) -N- (1- (4- (3-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 8 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 9 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 10 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 11 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 12 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 13 (R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 14 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (4-bromobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 15 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 16 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 17 (R) -N- (1- (4,5-bis (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- ( 1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 18 (S) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 19 (R) -N- (1- (4- (3-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 20 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 21 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3,5-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 22 (R) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 23 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 24 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5- (3- (1H-indol-3-yl) propyl) -4H-1, 2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 25 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2-methoxy) benzyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 26 (R) -N- (1- (4- (2-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 27 (R) -N- (2- (1H-indol-3-yl) -1- (4- (naphthalen-1-ylmethyl) -5-phenethyl-4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 28 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3,4-dichlorobenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 29 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-fluorobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 30 (R) -N- (1- (4- (4-fluorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 31 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,

Compound 32 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,

Compound 33 (R) -N- (1- (4- (4-methylbenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 34 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methylbenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 36 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-2-carboxamide,

Compound 37 (R) -N- (1- (4- (4-methylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 38 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminobenzamide,

Compound 39 (R) -N- (1- (5-benzyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 40 (2S, 4R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -4-hydroxypyrrolidine-2-carboxamide,

Compound 41 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,

Compound 42 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,

Compound 43 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 44 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) piperidine-4-carboxamide,

Compound 45 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,

Compound 46 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 47 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 48 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,

Compound 49 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,

Compound 50 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminoacetamide,

Compound 51 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-2-yl) acetamide,

Compound 52 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-4-yl) acetamide,

Compound 53 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) cyclohexanecarboxamide,

Compound 54 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,

Compound 55 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,

Compound 56 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -3-aminopropanamide,

Compound 57 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-aminopropanamide,

Compound 58 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-3-yl) acetamide,

Compound 59 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -3- (pyridin-3-yl) propanamide,

Compound 60 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,

Compound 61 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,

Compound 62 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) piperidine-4-carboxamide,

Compound 63 (R) -N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) piperidine-2-carboxamide,

Compound 64 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) picolinamide,

Compound 65 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) isonicotinamide,

Compound 66 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) pyrazine-2-carboxamide,

Compound 67 (R) -N-1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) piperazine-2-carboxamide,

Compound 68 (S) -N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 69 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,

Compound 70 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2, 4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 71 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) pyrazine-2-carboxamide,

Compound 72 (R) -N-1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) piperazine-2-carboxamide,

Compound 73 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) picolinamide,

Compound 74 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) ethanamine,

Compound 75 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-aminoacetamide,

Compound 76 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) pyrazine-2-carboxamide,

Compound 77 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) isonicotinamide,

Compound 78 (R) -N-1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) piperazine-2-carboxamide,

Compound 79 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) picolinamide,

Compound 80 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) picolinamide,

Compound 81 (R) -N-1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-Indol-3-yl) ethyl) piperazine-2-carboxamide,

Compound 82 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-2-yl) acetamide,

Compound 83 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) piperidine-4-carboxamide,

Compound 84 (R) -N-1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) piperazine-2-carboxamide,

Compound 85 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) pyrazine-2-carboxamide,

Compound 86 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-cis-aminocyclohexanecarboxamide,

Compound 87 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,

Compound 88 (R) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-2-carboxamide,

Compound 89 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 90 (R) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 91 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,

Compound 92 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-bromobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 93 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2-phenylethyl) -2-amino-2-methylpropanamide,

Compound 94 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (thiophen-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) piperidine-4-carboxamide,

Compound 95 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 96 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 97 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 98 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 99 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 100 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-methyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 101 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 102 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 103 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 104 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 105 (R) -N- (1- (5-benzyl-4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,

Compound 106 (R) -N- (1- (5-benzyl-4- (2,2-diphenylethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 107 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,2-diphenylethyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 108 (R) -N- (1- (4- (3,5-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 109 (R) -N- (1- (4,5-dibenzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino -2-methylpropanamide,

Compound 110 (R) -N- (1- (5-benzyl-4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,

Compound 111 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 112 (S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 113 (R) -N- (1- (4- (3,5-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 114 (R) -N- (1- (4- (4-bromobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 115 (R) -N- (1- (4- (2-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 116 (S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 117 (R) -N- (1- (4,5-diphenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino -2-methylpropanamide,

Compound 118 (R) -N- (1- (4- (3,4-dichlorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 119 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) ethanamine,

Compound 120 (R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2-phenylethyl) -2-amino- 2-methylpropanamide,

Compound 121 (R) -N- (1- (4- (4-fluorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 122 (R) -N- (1- (4- (3,4-dichlorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 124 (R) -N- (1- (4- (4-methylbenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 125 (S) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 126 (S) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 128 N-((R) -1- (4-nitrobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 129 (S) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 130 (R) -N- (1- (4- (4-methoxyphenethyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 131 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (thiophen-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 132 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 133 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) piperidine-3-carboxamide,

Compound 134 (S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 135 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminoacetamide,

Compound 136 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-4-yl) acetamide,

Compound 137 (2R) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,

Compound 138 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) picolinamide,

Compound 139 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminopyridine-3-carboxamide;

Compound 140 (2S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-aminopropanamide,

Compound 141 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) isonicotinamide,

Compound 142 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) piperidine- 4-carboxamide,

Compound 143 (2S) -N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) Ethyl) pyrrolidine-2-carboxamide,

Compound 144 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) -2 -Aminoacetamide,

Compound 145 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) -2 -(Pyridin-2-yl) acetamide,

Compound 146 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) picolinamide ,

Compound 147 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) picolinamide,

Compound 148 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,

Compound 149 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,

Compound 150 (2S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,

Compound 152 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,

Compound 153 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-trans-aminocyclohexanecarboxamide,

Compound 154 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-3-yl) acetamide,

Compound 155 (3S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,

Compound 156 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminobenzamide,

Compound 157 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) picolinamide,

Compound 158 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,

Compound 159 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) picolinamide,

Compound 160 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3 -Yl) ethyl) -2- (pyridin-2-yl) acetamide,

Compound 161 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) pyrazine-2-carboxamide,

Compound 162 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) -2-aminoacetamide,

Compound 163 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) piperidine-4-carboxamide,

Compound 164 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) picolinamide,

Compound 165 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-acetamide,

Compound 166 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-4-carboxamide,

Compound 167 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 168 N-((R) -1- (5- (4-methoxybenzyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,

Compound 169 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) picolinamide,

Compound 170 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-acetamide,

Compound 171 (R) -benzyl-3- (2-aminoisobutyramide) -3- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1 , 2,4-triazol-3-yl) -propanoate,

Compound 172 N-((R) -1- (5-benzyl-4-((pyridin-3-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 173 N-((R) -1- (4-benzyl-5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,

Compound 174 N-((R) -2- (1H-indol-3-yl) -1- (4-methyl-5-phenethyl-4H-1,2,4-triazol-3-yl) ethyl) picolinamide ,

Compound 175 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 176 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) benzamide,

Compound 177 (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) -N-phenylmethanesulfonylamine,

Compound 178 (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) -N-tosyl ethanamine,

Compound 179 N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,

Compound 180 N-1-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) ethane-1,2-diamine,

Compound 181 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 182 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) picolinamide,

Compound 183 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-4-carboxamide,

Compound 184 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -tetrahydro-2H-pyran-4-carboxamide;

Compound 185 N-((R) -1- (5-((1H-indol-3-yl) methyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,

Compound 186 (2S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-3-phenylpropanamide,

Compound 187 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) -N-tosylethanamine,

Compound 188 N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -4-azidobenzamide,

Compound 189 N-benzyl- (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole- 3-yl) etanamin,

Compound 190 (2S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2,5-dihydro-1H-pyrrole-2-carboxamide,

  To avoid uncertainty, if the chemical name and chemical structure of the above described compound do not correspond by 瑕疵, the chemical structure is considered to clearly define the compound.

  In a preferred embodiment, these compounds can be used for the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals mediated by GHS receptors.

  In a further preferred embodiment, all the triazole compounds described herein, i.e. generally (depending on formula (I) above and various R groups) and explicitly below, the compounds of the invention For the treatment or prevention of a physiological and / or pathophysiological condition in a mammal mediated by the GHS receptor, the treatment of which is achieved by modulation of the GHS receptor Can be used for the manufacture of pharmaceuticals.

  In yet another preferred embodiment, all the compounds of the invention are antagonists of the GHS receptor.

  More preferably, the antagonist of GHS receptor is compound 1, 3, 12, 13, 14, 18, 20, 22, 23, 33, 36, 37, 41, 46, 47, 48, 49, 50, 51, 52, 53, 57, 58, 59, 60, 61, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 82, 85, 86, 87, 88, 89, 90, 91, 93, 101, 102, 109, 114, 116, 119, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 150, 152, 153, 154, 156, 157, 159, 160, 161, 164, 171, 174, 176, 178, 179, 182, 184, 186, 188 and / or 190 It is a compound selected from.

  In yet a further preferred embodiment, all compounds of the invention are agonists of the GHS receptor.

  More preferably, the agonist of GHS receptor is compound 2, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 17, 19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 39, 40, 42, 43, 44, 45, 54, 55, 56, 62, 67, 78, 81, 83, 84, 87, 92, 94, 99, 103, 104, 105, 106, 107, 108, 110, 111, 115, 117, 118, 121, 122, 124, 130, 131, 142, 155, 158, 163, 173, 175, 180, 181, 183, 185 and And / or a compound selected from the group consisting of 187.

The terms indicated in the description of said compounds of general formula (I) always have the following meanings unless otherwise stated in the description or in the claims:
The term “substituted” means that the corresponding residue or group has one or more substituents. Where a residue has multiple substituents and various substituent options are specified, the substituents are selected independently of each other and need not be the same. The term “unsubstituted” means that the corresponding group has no substituent. The term “optionally substituted” means that the corresponding group is either unsubstituted or substituted by one or more substituents. The term “substituted by up to 3 substituents” means that the corresponding residue or group is substituted by either 1 substituent or 2 or 3 substituents.

The term “alkyl” for the purposes of the present invention includes acyclic, saturated, C ₁ -C ₁₂ carbon atoms, which may be linear or branched. The term “alkyl” preferably represents an alkyl chain of 1 to 8, particularly preferably 1 to 6 carbon atoms. Examples of suitable alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, t-pentyl, 2- or 3-methyl-pentyl, n -Hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl.

The term “cycloalkyl” has 1 to 3 saturated or partially unsaturated non-aromatic rings and 3 to 20 carbon atoms in total, preferably 3 to 10 carbon atoms forming the ring. cyclic hydrocarbon group (monocyclic alkyl, including bicyclic alkyl and tricyclic alkyl), most preferably C ₃ -C ₈ - cycloalkyl. Examples of suitable cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctadienyl and the like.

The term “cycloalkylalkyl” refers to a group in which the cycloalkyl group is linked via an alkyl group, the alkyl group and the cycloalkyl group having the meanings defined herein, preferably C ₃ -C ₈ -cyclo. It refers to an alkyl group - alkyl -C ₁ -C _4. Examples thereof are cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexenylethyl.

The term “alkenyl” for the purposes of the present invention has an acyclic unsaturated or partially unsaturated, C ₂ -C ₁₂ carbon atom and may be linear or branched. And hydrocarbons which may have one or more double bonds. The term “alkenyl” preferably represents an alkenyl chain of 2 to 8, particularly preferably 2 to 6 carbon atoms. Examples are vinyl, propenyl, butenyl, pentenyl, hexenyl and octadienyl.

The term “alkynyl” has an acyclic unsaturated or partially unsaturated, C _{2 to} C ₁₂ carbon atom, which may be linear or branched and contains one or more triple bonds. Refers to hydrocarbons that may be present. The term “alkynyl” preferably represents an alkynyl chain of 2 to 8, particularly preferably 2 to 6 carbon atoms. Examples are propynyl, butynyl, pentynyl, hexynyl.

  The term “aryl” is an aromatic hydrocarbon system having 3 to 14, preferably 5 to 14, carbon atoms, fused to a further saturated, (partially) unsaturated or aromatic ring system. It refers to what you may have. Examples of “aryl” are inter alia phenyl, biphenyl, naphthyl and anthracenyl, but also indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl.

  The term “heteroaryl” is a 5-membered, 6-membered or 7-membered cyclic aromatic group, comprising at least 1, optionally 2, 3, 4 or 5 heteroatoms, preferably A group having nitrogen, oxygen and / or sulfur, wherein the heteroatoms are the same or different. The number of nitrogen atoms is preferably 0 to 3, and the number of oxygen atoms and sulfur atoms is 0 to 1. The term “heteroaryl” also refers to a system in which the aromatic ring is part of a bicyclic or polycyclic system, eg, an aromatic ring as defined herein for an aryl, cycloalkyl, heteroaryl or heterocyclic group. Also includes systems fused via any desired possible ring member of a heteroaryl group. Examples of “heteroaryl” include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl and isoquinolinyl.

The terms “arylalkyl” and “heteroarylalkyl” refer to a group in which an aryl or heteroaryl group is attached via an alkyl group, the alkyl, aryl and heteroaryl groups having the meanings defined herein. Preferred “arylalkyl” groups are phenyl-C ₁ -C ₄ -alkyl groups, preferably benzyl or phenylethyl groups. Preferred “heteroarylalkyl” groups are indolyl-C ₁ -C ₄ -alkyl groups, preferably 1H-indol-3-yl-methyl or 2- (1H-indol-3-yl) -ethyl.

  The term “heterocyclyl” refers to a monocyclic or polycyclic ring system of 3 to 14, preferably 5 or 6 to 14 ring atoms, which may be exclusively carbon atoms. However, the ring system may also contain 1, 2, 3, 4 or 5 heteroatoms, in particular nitrogen, oxygen and / or sulfur. The ring system may be saturated, monounsaturated or polyunsaturated, but need not be aromatic. In the case of a ring system consisting of at least two rings, the rings may be fused or spiro or other bonds may be made. A “heterocyclyl” group may be attached at any carbon or heteroatom that results in a stable structure. Examples include pyrrolidinyl, thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl and oxadiazolyl.

  The term “heterocyclylalkyl” refers to a group in which a heterocyclyl group is attached via an alkyl group, wherein the alkyl group and the heterocyclyl group have the meanings defined herein.

The terms “alkylsulfonyl”, “arylsulfonyl” and “arylalkylsulfonyl” mean that an alkyl, aryl or arylalkyl group is attached via a —SO ₂ — group, wherein said alkyl, aryl and arylalkyl groups Refers to a group having the meaning as defined herein. Examples are methylsulfonyl and phenylsulfonyl.

  The terms "halogen", "halogen atom" or "halogen substituent" (Hal-) refer to a single, optionally multiple, fluorine (F, fluoro) atom, bromine (Br, bromo) atom, chlorine (Cl, chloro ) Atom or iodine (I, iodo) atom. The notations "dihalogen", "trihalogen" and "perhalogen" are 2, 3 and 4 substituents, respectively, each substituent being unrelated from the group consisting of fluorine, chlorine, bromine and iodine. Refers to a substituent that can be selected. “Halogen” advantageously means a fluorine, chlorine or bromine atom.

  The term “neutral α-amino acid side chain” for the purposes of the present invention refers to all side chains of the known 20 proteogenic α-amino acids as well as naturally occurring (ie any biological system). Α-amino acids such as selenocysteine, pyrrolidine, citrulline, ornithine, homocysteine, N-methylarginine, N-acetyllysine, γ-carboxyglutamate, 5-hydroxylysine, 3-methylhistidine and / or N, N, Refers to the side chain of N-trimethyllysine. In this context, “side chain” refers to a residue attached to the α-carbon, such as methyl for the Ala side chain or benzyl for the Phe side chain.

  For the purposes of the present invention, the term “non-neutral α-amino acid side chain” is not proteogenic and is not known to occur in nature (ie in any biological system) Refers to all side chains of α-amino acids. Examples are norleucine, cyclohexylglycine, 2-naphthylalanine, substituted α-amino acids (eg halogen-substituted Tyr or Phe) as well as protected α-amino acid side chains, with protecting groups such as Fmoc, Boc, Z, CBZ, Aloc, trityl, acetyl and / or benzyl are directly coupled / reacted to functionalize (eg, amino, hydroxy and / or carboxy residues). In this context, “side chain” refers to “neutral α-amino acid side chain”.

Functionalized (e.g. amino, hydroxy and / or carboxy residues) above embodiments in group R1~R10 having, for example, alkyl -CO-NH _2, - alkyl -CO-OH, - alkyl -NH _2, - alkyl - _{NH-C (NH) -NH 2} , -CO-C * (R9R10) -NH 2, -CO-CH 2 -C * (R9R10) -NH 2, -CO-C * (R9R10) -CH 2 -NH ₂ and / or 2-amino-2-carbonyl-propane (2-amino-isobutyric acid / Aib residue) may be protected with a protecting group as described above. Embodiments having such protecting groups are within the scope and spirit of the present invention and are considered to be within that scope.

  All stereoisomers of the compounds of the invention are considered in the mixture or in pure or substantially pure form. The compounds of the present invention may have asymmetric centers at any carbon atom containing any one of the R groups. Thus, the compounds of the invention may exist in their racemic form, in the form of pure enantiomers and / or diastereomers, or in the form of mixtures of these enantiomers and / or diastereomers. The mixture may have any desired mixing ratio of stereoisomers. All these various stereochemical forms and mixtures are within the scope of the present invention.

  Thus, for example, compounds of the present invention which have one or more chiralities and occur as racemates or diastereomeric mixtures can be separated by methods known per se and optically resolved. Pure isomers, ie enantiomers or diastereomers, can be obtained. Resolution of the compounds of the invention can be achieved by column resolution in chiral or non-chiral phases, or by recrystallization, optionally from optically active solvents or with optically active acids or bases, or optically active reagents such as optical It can be carried out by derivatization with an active alcohol followed by elimination of the group.

  If possible, the compounds of the invention may be in the form of tautomers.

  Similarly, the compounds of the present invention may be in any desired prodrug form, such as an ester, carbonate or phosphate form, in which case it is in a biologically active form only through metabolism. Is released. Any compound that can be converted in vivo to provide a bioactive agent (ie, a compound of the invention) is a prodrug within the scope and spirit of the invention.

Various forms of prodrugs are well known in the art and are described, for example, in (i)-(iii) below:
(I) The Practice of Medicinal Chemistry (Wermuth CG et al., Chapter 31, Academic Press 1996);
(Ii) Design of Prodrugs (Editor: Bundgaard H, Elsevier 1985); and (iii) A Textbook of Drug Design and Development P. Academic Publishers 1991).

  The above references are disclosed by reference.

  Furthermore, it is known that chemicals are converted into metabolites in the body, which, if appropriate, manifest the desired biological effects even in more pronounced forms in some environments as well.

  Any biologically active compound converted from any compound of the present invention by metabolism in vivo is a metabolite within the scope and spirit of the present invention.

  The compounds of the present invention can be converted using inorganic and organic acids if they have a sufficiently basic group such as a primary, secondary or tertiary amine to convert the salt Obtainable. The pharmaceutically acceptable salts of the compounds of the invention are preferably hydrochloric, hydrobromic, iodic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, sulfo Acetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid Alternatively, it is formed using aspartic acid. The salts formed are, among others, hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate, tosylate, carbonate, bicarbonate, formate, Acetate, sulfoacetate, trifluoromethanesulfonate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate Citrate, glutarate, stearate, aspartate and glutamate. The stoichiometry of the salts formed from the compounds of the present invention may further be an integer multiple or non-integer multiple of 1.

  The compounds of the present invention can be converted using inorganic and organic bases if they have a sufficiently acidic group, such as a carboxy group, a sulfonic acid group, a phosphoric acid group or a phenolic group, and their physiology. Acceptable salts can be obtained. Examples of suitable inorganic bases are ammonium, sodium hydroxide, potassium hydroxide, calcium hydroxide, and examples of organic bases are ethanolamine, diethanolamine, triethanolamine, ethylenediamine, t-butylamine, t-octylamine. Dehydroabiethylamine, cyclohexylamine, dibenzylethylene-diamine and lysine. The stoichiometry of the salts formed from the compounds of the present invention may further be an integer multiple or non-integer multiple of 1.

  Similarly, the compounds of the present invention may be in the form of their solvates, especially hydrates, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In addition, one, two, three or any number of solvates or water molecules can be combined with the compounds of the invention to give solvates and hydrates.

  A chemical forms a solid that exists in various ordered states, referred to as polymorphs or polymorphic transformations. The various transformations of polymorphic substances can vary greatly in their physical properties. The compounds of the invention may exist in various crystalline polymorphs, and certain modifications may be transferable. All these crystalline polymorphs of the compounds of the present invention should be considered as belonging to the present invention.

  The triazole derivatives (compounds according to the invention) described herein are ghrelin analog ligands of the GHS receptor. Thus, said compounds of the invention are influenced by physiological and / or pathophysiological conditions mediated by GHS receptors and / or modulation of these receptors, thus preventing, treating and Suitable for the treatment or prevention of physiological and / or pathophysiological conditions that can be alleviated.

  For the purposes of the present invention, the term “treatment” is also intended to include prophylactic treatment or alleviation.

  The term “ghrelin analog ligand” or “ligand” binds to a receptor in any manner for purposes of the present invention, where the receptor in the present invention is a GHS receptor, and Refers to any compound that activates, inhibits and / or induces other possible effects at this receptor. Thus, the term “ghrelin analog ligand” or “ligand” is an agonist, antagonist, partial agonist / antagonist, inverse agonist and other ligand similar to the action of an agonist, antagonist, partial agonist / antagonist or inverse agonist. A ligand that causes the receptor to act at the receptor.

  For the purposes of the present invention, the term “GHS receptor antagonist” or “GHS receptor antagonist” is a compound of the invention, which binds to a GHS receptor but is a G protein-coupled receptor (GPCRs). ) Activation does not reveal the original activation of the receptor, as assessed by a record of the increase in intracellular calcium characteristic.

The ability to properly activate the receptor is determined by the degree of activation of GHS-R1a (increase in intracellular calcium) by the compound to be tested (at a concentration of 10 ⁻⁶ M) for any compound of the invention. It is assessed by comparing the extent of activation of GHS-R1a (increased intracellular calcium) by 10 ⁻⁶ M ghrelin (100%) and basal levels (0%). Such evaluation can be easily carried out by those skilled in the art with their expertise. The output is a percentage value for each compound to be tested.

  Any compound of the present invention that does not show a degree of activation of GHS-R1a (increased intracellular calcium) of at least 20% as assessed according to the above specifications does not reveal adequate activity and is therefore a GHS receptor antagonist Considered as. Advantageously, such compounds do not show antagonism (antagonism / reduction) to ghrelin, and an increase in intracellular calcium stimulated by other GHS suppresses such stimulation or even acts as an inverse agonist ( An inverse agonist binds to the same receptor binding site as an agonist or antagonist, but causes an inhibition of the basal / constitutive activity of the receptor and is essentially an agonist with negative intrinsic activity). Furthermore, such compounds may exhibit inhibitory activity on GH secretion and / or on other physiological or pathophysiological conditions or effects such as feeding behavior or adipogenesis. These effects may be separated. Thus, these compounds can inhibit other physiological effects without any effect on GH secretion. These compounds may stimulate other physiological effects.

  For the purposes of the present invention, the term “GHS receptor agonist” or “GHS receptor agonist” is a compound of the invention, which binds to a GHS receptor and activates a G protein coupled receptor. Refers to the manifestation of proper activation of the receptor as assessed by a record of the characteristic intracellular calcium increase.

  Any compound of the present invention that exhibits a degree of activation of GHS-R1a (increased intracellular calcium) of at least 20% as assessed according to the above specifications does not reveal adequate activity and is therefore as a GHS receptor agonist Considered. Such compounds may mimic GH secretion and, for example, the effects of ghrelin and / or GHS on feeding behavior or adipogenesis. As with antagonists, the action of the agonist compound may be separated from the GH secretion action. Such compounds may also antagonize (antagonize / reduce) intracellular calcium increases stimulated by ghrelin and / or other GHS.

  The term “GHS receptor” or “GHS-R” for the purposes of the present invention includes receptors that bind at least one known peptidic and / or non-peptidic GHS and / or ghrelin. Is intended. The term “GHS receptor” or “GHS-R” also refers to various GHS binding sites in the various tissues and / or organs described herein, wherein at least one known peptidic and / or It is also intended to include those that bind non-peptidic GHS and / or ghrelin and are probably the uncharacterized GHS-R subtype.

  The binding of a given known peptidic and / or non-peptidic GHS and / or ghrelin is easily verified by a person skilled in the art, for example by means of a suitable binding assay which only represents a routine experiment. Can do.

  Such GHS receptors may be stimulated / activated by ghrelin for each of acylated and non-acylated ghrelin (ghrelin responsiveness), or may not be stimulated / activated by ghrelin (Ghrelin non-responsiveness). Although stimulation / activation of such receptors may occur, it does not necessarily reveal GH protection and / or GH secretion and / or increase GH plasma levels.

  Advantageously, such GHS receptors are “GHS type 1 receptor, GHS-R1a, GHS-R1b, motilin receptor, motilin receptor Ia, neurotensin receptor, TRH receptor, GPR38 (FM1), GPR39 ( FM2), FM3, GHS binding site, GHS-R subtype, cardiac GHS-R, breast GHS-R ".

  More preferably, such a GHS receptor is selected from the group consisting of “GHS type 1 receptor, GHS-R1a, GHS-R1b”, most advantageously GHS-R1a.

  As discussed herein, GHS receptors (including GHS binding sites and GHS-R subtypes) are known to be concentrated in the hypothalamic-pituitary region, but other It is also likely to be distributed in central and peripheral tissues. Furthermore, these receptors are also expressed in various tumor tissues, even in tumor tissues from organs that do not express these receptors under physiological conditions.

  For the purposes of the present invention, organs and / or tissues that express all these GHS receptors (including GHS binding sites and GHS-R subtypes) are intended to be encompassed by the scope of the present invention. The Expression of GHS receptors (including GHS binding site and GHS-R subtype) in a given organ and / or tissue is preferred by those skilled in the art based on their expertise, eg, representing only routine experiments. It can be easily verified by molecular biological assays such as immunofluorescence assays or immunoprecipitation assays.

  Preferably, such GHS receptors are “endocrine tissue, exocrine tissue, peripheral tissue, fat / lipid tissue, brain, hypothalamus, thalamus, hippocampus, striatum, cortex, pituitary gland, central nervous system, spinal cord, gland, adrenal gland. , Thyroid, salivary gland, mammary gland, neuron, intestine, intestine, stomach, heart, liver, pancreas, kidney, bile, gall, bladder, prostate, spleen, muscle, skeletal muscle, aorta, artery, vein, Immune cells, leukocytes, lymphocytes, T cells, B cells, granulocytes, monocytes, macrophages, dendritic cells, mast cells, NK cells, neutrophils, eosinophils, basophils, lymph nodes, bone, bone marrow A tissue selected from the group consisting of: amygdala, thymus, placenta, testis, ovary, uterus, lung, adipocyte, tumor cell / cancer cell, carcinoma cell, prostate cancer cell, thyroid cancer cell, lung cancer cell, breast cancer cell And / or located in an organ.

  As explained above, the compounds of the present invention are ghrelin analog ligands of the GHS receptor. The compounds can be administered to various mammalian species, including humans, to treat or prevent physiological and / or pathophysiological conditions in such mammals.

  For the purposes of the present invention, all mammalian species are considered to be included. Preferably, such mammals are “human, domestic animals, cattle, domestic animals, pets, cows, sheep, pigs, goats, horses, ponies, donkeys, chicks, mules, hares, rabbits, cats, dogs, guinea pigs, hamsters, Selected from the group consisting of "rat, mouse". More preferably, such mammal is a human.

The compounds of the present invention that are non-peptidic ghrelin analog ligands of the GHS receptor are surprisingly characterized by strong binding affinity for such receptors. Such compounds may, for example, advantageously exhibit an IC ₅₀ value of less than 1000 nM for binding to GHS-R1a. More preferably, such compounds may exhibit an IC ₅₀ value of less than 500 nM, even more advantageously an IC ₅₀ value of less than 300 nM, most advantageously an IC ₅₀ value of less than 100 nM for binding to GHS-R1a. .

  Because of its surprisingly strong receptor binding, the compounds of the present invention preferably have the same or better desired even when administered at lower doses compared to other less potent binding agents. Biological effects can be achieved. Furthermore, such dose reductions preferably may result in lower or no pharmacological side effects. Furthermore, the high binding specificity of the compounds of the invention can be paraphrased as a reduction in unwanted side effects, regardless of the dose applied.

  Furthermore, the compounds of the present invention are non-peptidic in nature, but are resistant to enzymatic degradation of the gastrointestinal tract. These compounds therefore offer the advantage of being administered by the oral route. The compounds surprisingly exhibit improved metabolic stability and / or improved biocompatibility. Thus, once again, a favorable dose reduction can be achieved that reduces the occurrence of side effects or may not even cause side effects.

  The compounds of the present invention may be either GHS antagonists or agonists as described and defined herein.

  The GHS receptor antagonists of the present invention can be used, for example, for inhibition of GHS receptors stimulated by ghrelin and / or other GHS, thus producing GH production and / or secretion and / or GH plasma levels. Is reduced and / or blocked. Furthermore, such GHS receptor antagonists may also be used for the inhibition or prevention of the physiological or pathophysiological effects of ghrelin that are not associated with GH production and / or GH secretion.

  Accordingly, the GHS receptor antagonists of the present invention are particularly useful for the treatment and / or prevention of various physiological and pathophysiological conditions disclosed herein, especially for short, medium and / or energy balance. Or for long-term regulation, for short-, medium- and / or long-term regulation (stimulation and / or inhibition) of eating behavior, for the treatment of adipogenesis, adiposity and / or obesity Suitable for weight gain and / or reduction and for the treatment of tumor cell proliferation.

  Conversely, the GHS receptor agonists of the present invention can be used, for example, for activation of the GHS receptor and for stimulation / increase of GH production and / or secretion, and thus growth hormone As such, it has the same action or use as ghrelin and / or known GHS.

  Thus, the GHS receptor agonists of the present invention are particularly useful for the treatment and / or prevention of various physiological and pathophysiological conditions disclosed herein, particularly growth retardation, cachexia, inflammation. Suitable for inflammatory action, gastric postoperative ileus, postoperative ileus and / or gastrectomy.

  For the purposes of the present invention, all physiological and / or pathophysiological conditions are intended to include those known to be mediated by GHS receptors.

  Preferably, these physiological and / or pathophysiological conditions are “acute fatigue syndrome and muscle degeneration after selection surgery, adipogenesis, adiposity, age-related decline in thymic function, in the elderly. Reduced aging function ("ARFD"), aging disease in domestic animals, Alzheimer's disease, loss of appetite (eg associated with cachexia or aging); anxiety, blood pressure (decreased), weight gain / loss, fracture repair (promotion) ), Bone remodeling stimulation, cachexia and protein deficiency due to chronic diseases such as cancer or AIDS, cardiac dysfunction (eg associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure), cardiomyopathy, cartilage Catabolism related to growth stimulation, pulmonary dysfunction and ventilation dependence, catabolic side effects of glucocorticoids, catabolic status of aging, central nervous system diseases Chronic dialysis, chronic fatigue syndrome (CFS), cognitive improvement (eg in dementia, Alzheimer's disease), concomitant fractures (eg bone extension), transplant-related complications, congestive heart failure ( Alone / in combination with a corticotropin-releasing factor antagonist), Crohn's disease and ulcerative colitis, Cushing syndrome, dementia, depression, short-term, moderate and / or long-term regulation of energy balance, short-term feeding behavior Moderate and / or long-term regulation (stimulation and / or inhibition), frailty (eg elderly humans), gastrectomy (ghrelin replacement therapy), gastric postoperative ileus, improved glycemic control, growth hormone in the elderly Release stimulation, growth hormone replacement in stressed patients, growth promotion in livestock, Prader-Willi syndrome and Turner Growth delays associated with symptoms, growth retardation associated with Crohn's disease, growth retardation, hair / nail growth maintenance, hip fracture, hunger, hyperadrenocorticism, hyperinsulinism including islet cell disease, hypothermia, Immunodeficiency in individuals with suppressed T4 / T8 cell ratio, improvement of immune response to vaccine, immune system stimulation in livestock, immune system stimulation, immunosuppression in immunosuppressed patients, inflammation or inflammatory effects, inflammatory bowel disease Insulin resistance in the heart, insulin resistance in type 2 diabetes, NIDDM, diabetes, type 1 diabetes, insulin resistance including type 2 diabetes, intrauterine growth retardation, irritable bowel syndrome, lipodystrophy (eg, HIV-induced), Maintaining metabolic homeostasis, increasing milk production in livestock, increasing muscle mass / muscle strength, improving muscle motility, improving muscle strength, Maintenance of muscle strength / function in aged humans, muscle atrophy, musculoskeletal disorders (eg in the elderly), Noonan syndrome, obesity and growth retardation associated with obesity, osteoblast stimulation, osteochondral dysplasia, osteoporosis, ovulation induction (Adjuvant treatment), physiological short stature, including children with growth hormone deficiency, postoperative ileus, attenuation of protein catabolism after major surgery / trauma, increased protein kinase B activity, psychosocial disturbance, pulmonary dysfunction and ventilation dependence , Improvement of lung function, induction of pulsatile growth hormone release, recovery of burn patients and reduction of hospitalization (promotion) of burn patients, renal failure or renal dysfunction resulting from growth delay, maintenance of kidney homeostasis of debilitated elderly, muscle loss Schizophrenia, sensory function maintenance (eg hearing, visual acuity, smell and taste), short bowel syndrome, short stature associated with chronic disease, skeletal dysplasia, skin thickness maintenance, sleep Sleep disorders, improved sleep quality, thrombocytopenia, thymic stimulation, dental repair or growth, tumor cell proliferation, ventricular dysfunction or reperfusion event, weakness associated with AIDS, weakness associated with chronic liver disease, chronic Weakness associated with obstructive pulmonary disease (COPD), weakness associated with multiple sclerosis or other neurodegenerative diseases, secondary weakness to fractures, stimulation of wool growth in sheep, wound healing (promotion), delayed wound healing Selected from the group consisting of: More preferably, these physiological and / or pathophysiological states are: “growth retardation, cachexia, short-term, medium- and / or long-term regulation of energy balance; short-term feeding behavior; Medium and / or long-term regulation (stimulation and / or inhibition); adipogenesis, adiposity and / or obesity; weight gain and / or decline; diabetes, type 1 diabetes, type 2 diabetes, tumor cell proliferation; inflammation , Inflammatory action, postoperative ileus of the stomach, postoperative ileus and / or gastrectomy (ghrelin replacement therapy) ”.

  In a further aspect of the invention, the compounds of the invention can be used in combination with at least one additional pharmacologically active substance.

  Such additional pharmacologically active substances may be other compounds of the invention and / or other “suitable treatments” useful in the treatment and / or prevention of said physiological and / or pathophysiological conditions. Agent ". The additional pharmacologically active substance may be a GHS receptor antagonist and / or a GHS receptor agonist, depending on the purpose of the combination use. The selection and combination of additional pharmacologically active substances is easily carried out by those skilled in the art based on their expertise and depending on the purpose of the combination use and the physiological and / or pathophysiological targeted condition. Can be implemented.

  In a preferred embodiment, the compounds of the invention comprise at least one additional pharmacologically active substance for the treatment and / or prevention of said physiological and / or pathophysiological conditions. Is used in the form of pharmaceuticals.

  In another preferred embodiment, the compounds of the invention are used at least before and / or during and / or after treatment for the treatment and / or prevention of said physiological and / or pathophysiological conditions. Used in the form of a pharmaceutical applied together with one additional pharmacologically active substance.

  The above-mentioned “suitable therapeutic agents” are “GHS, antidiabetic agent; anti-osteoporosis agent; anti-obesity agent; anti-inflammatory agent; anxiolytic agent; antidepressant agent; antihypertensive agent; antiplatelet agent; Thrombolytic agents; cardiac glycosides; cholesterol / lipid lowering agents; mineralocorticoid receptor antagonists; phosphodiesterase inhibitors; protein tyrosine kinase inhibitors; thyroid mimetics (including thyroid receptor antagonists); anabolic agents; HIV or AIDS therapeutics Therapeutic agents useful for the treatment of Alzheimer's disease and other cognitive disorders; therapeutic agents useful for the treatment of sleep disorders; antiproliferative agents; anti-tumor agents; anti-ulcer agents and gastroesophageal reflux disorder agents; progestin receptor agonists (" PRA "); estrogen; testosterone; selective estrogen receptor modulator; selective androgen receptor Ju aerator; parathyroid hormone; "comprises, advantageously" and / or bisphosphonate suitable therapeutic agents "is selected from the group consisting of said agents.

  Examples of GHS suitable for use in combination with the compounds of the present invention include GHRP-6, GHRP-1 and U.S. Pat. No. 4,411,890 and documents WO 89/07110 and WO 89/07111. B-HT920 or growth hormone releasing factor and analogs thereof or growth hormone and analogs thereof or somatomedins including IGF-1 and IGF-2 and GHS described in WO01 / 96300.

  Examples of anti-diabetic agents suitable for use in combination with the compounds of the present invention include biguanides (eg, metformin), glucosidase inhibitors (eg, acarbose), insulin (including insulin secretagogues or insulin sensitizers), meglitinides ( Repaglinide), sulfonylureas (eg glimepiride, glyburide and glipizide), biguanide / glyburide combinations (eg glucovans), thiozolidinediones (eg troglitazone, rosiglitazone and pioglitazone), PPARα-agonists, PPARγ-agonists, PPARα / γ -Dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2), such as those disclosed in US Pat. No. 6,548,529, glucagon Peptides containing 1 (GLP-1) and dipeptidyl peptidase IV (DP4) inhibitors.

  Examples of anti-osteoporosis agents suitable for use in combination with the compounds of the present invention are alendronate, risedronate, raloxifene, calcitonin, nonsteroidal progestin receptor agonists, RANK ligand agonists, calcium-sensing receptor antagonists, TRAP inhibitors Selective estrogen receptor modulators (SERM), estrogens and AP-1 inhibitors.

  Examples of anti-obesity agents suitable for use in combination with the compounds of the present invention include endocannabinoid receptor antagonists such as CB1 receptor antagonists such as rimonabant (1H-pyrazole-3-carboxamide, 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N-1-piperidinyl-, monohydrochloride; CAS Registry Number: 158681-13-1; SR-141716A; US Pat. No. 5,624,941) AP2 inhibitors, such as those disclosed in US Pat. No. 6,548,529, PPARγ-antagonists, PPARδ agonists and orlistat.

  Anti-inflammatory agents suitable for use in combination with the compounds of the present invention include prednisone, dexamethasone, embrel, cyclooxygenase inhibitors (ie, inhibitors of COX-1 and / or COX-2, such as NSAIDs, aspirin, indomethacin, ibuprofen, Piroxicam, naproxen, celebrex, biox), CTLA4-Ig agonist / antagonist, CD40 ligand antagonist, integrin antagonist, α4β7 integrin antagonist, cell adhesion inhibitor, interferon gamma-antagonist, ICAM-1, tumor necrosis factor (TNF) antagonist (eg Infliximab, OR1384), prostaglandin synthesis inhibitor, budesonide, clofazimine, C I-1493, CD4 antagonists (eg, priliximab), p38 mitogen activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors and therapeutic agents for the treatment of irritable bowel syndrome (eg, zeimac and Maxi-K openers such as those disclosed in US Pat. No. 6,184,231).

  Examples of suitable anxiolytic agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam and hydroxyzine pamoate.

  Examples of suitable antidepressants for use in combination with the compounds of the present invention include citalopram, fluoxetine, nefazodone, sertraline and paroxetine.

  Examples of antihypertensive agents suitable for use in combination with the compounds of the present invention include β-adrenergic blockers, calcium channel blockers (L and T types; such as diltiazem, verapamil, nifedipine, amlodipine and mybefradiii. ), Diuretics (eg chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methyl chlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrylic acid triclinaphene, chlorothalidon, furosemide, musolimine, bumetanide, triamtrenene , Amiloride, spironolactone), renin inhibitor, ACE inhibitor (eg captopril, zofenopril, fosinopril, enalapril, sera) Prills, silazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (eg losartan, irbesartan, valsartan), ET receptor antagonists (eg sitaxsentan, atrusentan and US Pat. No. 5,612,359) And compounds disclosed in US Pat. No. 6,043,265), dual ET / AII antagonists (eg, compounds disclosed in WO00 / 01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP) -ACE inhibitors) (eg omapatrilate and gemopatrilate) and nitrates.

  Examples of antiplatelet agents suitable for use in combination with the compounds of the present invention include GPIIb / IIIa blockers (eg abciximab, eptifibatide, tirofiban), P2Y12 antagonists (eg clopidogrel, ticlopidine, CS-747), thromboxane receptor Body antagonists (eg ifetroban), aspirin and PDE-III inhibitors (eg dipyridamole) in combination with or without aspirin.

  Examples of cardiac glycosides suitable for use in combination with the compounds of the present invention include digitalis and ouabain.

  Examples of cholesterol / lipid lowering agents suitable for use in combination with the compounds of the present invention are HMG-CoA reductase inhibitors [eg pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin or nisvastatin or nisvastatin) And ZD-4522 (also known as rosuvastatin or atorvastatin or bisastatin)], squalene synthase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, cholesterol absorption inhibitors and cholesterol ester transfer protein inhibitors (e.g. CP-529414).

  Examples of mineralocorticoid receptor antagonists suitable for use in combination with the compounds of the present invention include spironolactone and epielinone.

  Examples of phosphodiesterase inhibitors suitable for use in combination with the compounds of the present invention include PDEIII inhibitors such as cilostazol and PDEV inhibitors such as sildenafil.

  Examples of thyroid mimetics suitable for use in combination with the compounds of the present invention include thyrotropin, polythyroid, KB-130015 and dronedarone.

  Examples of anabolic agents suitable for use in combination with the compounds of the present invention include testosterone and SARMs.

  Examples of suitable therapeutic agents for HIV or AIDS for use in combination with the compounds of the present invention include indinavir sulfate, saquinavir, saquinavir mesylate, amprenavir, ritonavir, ritonavir / lopinavir combination, lamivudine, zidovudine , Lamivudine / zidovudine combination, zycitabine, didanosine, stavudine and megestrol acetate.

  Examples of therapeutic agents for the treatment of Alzheimer's disease and other cognitive disorders suitable for use in combination with the compounds of the present invention include donepezil, tacrine, levastigmine, 5HT6γ-secretase inhibitor, β-secretase inhibitor, SK channel blocker , Maxi-K blockers and KCNQ class blockers.

  Examples of therapeutic agents for the treatment of sleep disorders suitable for use in combination with the compounds of the present invention include melatonin analogs, melatonin receptor antagonists, ML1B agonists and GABA / NMDA receptor antagonists.

  Examples of suitable antiproliferative agents for use in combination with the compounds of the present invention include cyclosporin A, taxol, FK506 and adriamycin.

  Examples of suitable anti-tumor agents for use in combination with the compounds of the present invention include taxol, adriamycin, epothilones, cisplatin and carboplatin.

  Examples of estrogen receptor modulators suitable for use in combination with the compounds of the present invention include tamoxifen and raloxifene.

  Examples of selective androgen receptor modulators suitable for use in combination with the compounds of the present invention are described in Edwards, J. et al. P. Bio. Med. Chem. Let, 9, 1003-1008 (1999) and Hammann, L .; G. Another book, J.A. Med. Chem. 12, 210-212 (1999).

  Examples of bisphosphonates suitable for use in combination with the compounds of the present invention include MK-217 (alendronate).

  Said other therapeutic agent, when used in combination with a compound of the present invention, for example in an amount as indicated in a medical consultation reference (PDR) or in other amounts determined by those skilled in the art. Can do.

  In a preferred embodiment, the compounds according to the invention comprise endocannabinoids as additional pharmacologically active substances for the treatment and / or prevention of said physiological and / or pathophysiological conditions. Receptor antagonists, preferably CB1 receptor antagonists, most preferably rimonabant (1H-pyrazole-3-carboxamide, 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N- 1-piperidinyl-, monohydrochloride; CAS Registry Number: 158681-13-1; SR-141716A; US Pat. No. 5,624,941) and a GHS-R antagonist as a compound of the present invention Used in the form of pharmaceuticals.

  In another preferred embodiment, the compounds of the invention are used before and / or during and / or after treatment for the treatment and / or prevention of said physiological and / or pathophysiological conditions. Applied together with at least one additional pharmacologically active substance, wherein such additional pharmacologically active substance is an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, Most preferably rimonabant (1H-pyrazole-3-carboxamide, 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N-1-piperidinyl-, monohydrochloride; CAS Registry Number SR-141716A; U.S. Pat. No. 5,624,941) and the compound of the present invention is GHS-R Antagoni Is used in the form of a pharmaceutical is a door.

  The compounds of the present invention can be administered in a known manner. The route of administration may thus be any route that effectively transports the active compound to the appropriate or desired site of action, for example oral or parenteral, in particular topical, transdermal, transdermal. It may be pulmonary, intravaginal, nasal, parenteral or implanted. Oral administration is preferred.

  The compounds of the invention are optionally converted to a form that can be administered together with a pharmaceutically acceptable carrier or diluent and into a form mixed with them. Suitable excipients and carriers are described, for example, in Ullman's Encyclopedia of Technical Chemistry, Vol. 4, (1953), 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), 918 et seq. H .; v. Czetsch-Lindenwald, “Hilfstoffe pharmaziege and angelzende Gebiet”; Pharm. Ind. 2, 1961, 72 et seq. Dr. H. P. Fiedler, "Lexicon der Hilfstoffe pharma pharmazie, Kosmetik and angelzend Gebiet", Canter KG, Aulendorf in Werttemberg, 1971.

  Oral administration can be carried out, for example, in solid form, as tablets, capsules, gel capsules, coated tablets, granules or powders, but can also be carried out in the form of potable solutions. The compounds of the present invention are known and commonly used physiologically acceptable excipients and carriers such as gum arabic, talc, starch, sugars such as mannitol, methylcellulose, lactose, gelatin, for oral administration. Can be combined with surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors (eg essential oils). Moreover, the compound of this invention can be disperse | distributed and it can also be set as a microparticle, for example, a nanoparticle composition.

  Parenteral administration can be effected, for example, by intravenous, subcutaneous, intramuscular injection of sterile aqueous or oil solutions, by implants, or by ointments, creams or suppositories. Administration in a sustained release form is also possible as appropriate. The implant may comprise an inert material such as a biodegradable polymer or a synthetic silicone such as silicone rubber. Vaginal administration is possible, for example, by a ring. Intrauterine administration is possible using, for example, a diaphragm or other suitable intrauterine device. Transdermal administration is further provided using formulations and / or suitable measures, such as patches, particularly suitable for this purpose.

  This dosage can vary widely depending on the type and / or severity of the physiological and / or pathophysiological condition, the mode of administration, the age, sex, weight and sensitivity of the subject to be treated. Within the abilities of those skilled in the art, a “pharmacologically effective amount” of a compound of the invention and / or an additional pharmacologically active substance is determined. Administration can be carried out in a single dose or in multiple separate doses.

  Suitable unit doses are, for example, at least one active ingredient, i.e. a compound according to the invention, and optionally at least one additional pharmacologically active substance 0.001 mg to 100 mg per kg body weight of the patient.

  In another aspect, the invention provides compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 06, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, From 184, 185, 186, 187, 188, 189 and / or 190 That relates to pharmacologically effective amount of a pharmaceutical composition comprising at least one triazole compound selected from the group.

  In a further aspect, such pharmaceutical compositions may additionally contain at least one pharmaceutically acceptable carrier and / or excipient and / or at least one further It may contain a pharmacologically active substance.

  In a preferred embodiment, such further pharmacologically active substance is an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, most preferably rimonabant [1H-pyrazole-3-carboxamide, 5- ( 4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N-1-piperidinyl-, monohydrochloride].

  With regard to the pharmaceutical composition according to the invention, at least one of the above-mentioned triazole compounds is administered in a pharmacologically effective amount, preferably in a unit dose, for example in the above unit dose, particularly and preferably administered orally. Present in a dosage form that allows Furthermore, reference may be made to what has already been said regarding the possible use and administration of the compounds according to the invention.

General Synthetic Schemes Compounds of the present invention are prepared according to the following general synthetic schemes and according to relevant published literature known to those skilled in the art (eg, WO 00/54729 and references cited therein). be able to.

  The reagents and procedures exemplified for these reactions appear in the working examples below. Unless otherwise stated, the various substituents (groups) of the compounds have the same meaning as defined herein for formula (I).

  Amide bond formation (peptide coupling) is performed by standard peptide coupling procedures known in the art. Optionally, the reaction is carried out at room temperature in a solvent such as dichloromethane (DCM) at room temperature, benzotriazol-1-yl-oxytris (dimethylamino) phosphonium-hexafluorophosphate (BOP) (Castro B et al., Tetrahedron Lett. 1975, 14: 1219-1222) and a base such as N-methyl-morpholine or diisopropylethylamine.

  Vulcanization of the formed amide was carried out using Lawesson's reagent (Tetrahedron Lett. 2000, 41: 4965-4968 by Pons JF et al.).

  Cyclization: The resulting thioamide was then subjected to conditions (5 equivalents of hydrazide and 5 eq) with slight modifications to the conditions reported by Hitosuyanagi et al. (Hitotsuyanagi Y et al., J. Org. Chem. 2002, 67: 3266-3271). 1.1 equivalents of mercury (II) acetate in acetonitrile). Cyclization to the triazole was generally achieved within 3 hours. When hydrazine is not commercially available, it was prepared from its acid or methyl ester precursor by known methods.

  Deprotection of the t-butyloxycarbonyl group (Boc) was carried out in the acidic medium normally described at room temperature.

R5 is -CO-alkyl, -CO-cycloalkyl, -CO-cycloalkylalkyl, -CO-aryl, -CO-arylalkyl, -CO-heteroaryl, -CO-heteroarylalkyl, -CO-heterocyclyl, -CO- ^{heterocyclylalkyl, -CO-C * (R9R10)} -NH 2, -CO-CH 2 -C * (R9R10) -NH 2, -CO-C * (R9R10) -CH 2 -NH 2 (R) Is:

R5 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl (R):

R5 is alkyl -SO ₂ -, aryl -SO ₂ -, arylalkyl -SO ₂ - is a (R = alkyl, aryl, arylalkyl):

  Compounds of the present invention, especially compounds 1-190, were named from formulas drawn using Chem Draw Ultra 8 software (CambridgeSoft Corporation, Cambridge, USA).

BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1-13 show ¹²⁵ I-His ⁹ -ghrelin and selected compounds 9, 31, 39, 45, 50, 62, 64, 71, 73, 74, 79 of the Examples section. FIG. 7 shows measured competition plots of GHS-R1a receptor ligand binding assay at 81 and 90. FIG.

14-40 are selected compounds 1, 9, 12, 20, 22, 31, 39, 41, 42, 45, 46, 47, 48, 49, 50, described in Example section III). 51, 55, 62, 64, 67, 71, 73, 74, 79, 81, 90 and ghrelin calculated in vitro intracellular calcium release assay using human GHS-R1a transfected CHO cells. Dose-response plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown.

  FIGS. 41-46 show lipolysis induced by isoprorerenol of unacylated ghrelin (UAG) in primary adipocytes from mice with diet-induced obesity, as described in Examples VIII). The effect of selected compounds 9, 38, 50, 64, 74, 81 on the inhibition curve is shown.

  The contents of all references and patents are disclosed by reference. The present invention will be described in detail by the following examples, but is not limited to these examples.

Example I) Synthesis of compounds of the invention Example 1:
(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 1)
Compound 1 consists of Boc- (D) -Trp (10 mmol), (2,4-dimethoxyphenyl) methanamine, 3- (1H-indol-3-yl) propane hydrazide and Boc-2-amino-2-methylpropane Obtained from the acid in 35% overall yield after purification by HPLC according to the general synthetic scheme.

Example 2:
(R) -N- (1- (5-Benzyl-4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) -2-amino-2-methylpropanamide (Compound 4)
Compound 4 is prepared from Boc- (D) -Trp (10 mmol), naphthalen-1-yl-methanamine, 2-phenylacetohydrazide and Boc-2-amino-2-methylpropanoic acid according to the general synthetic scheme. Obtained in 42% overall yield after purification by HPLC.

Example 3:
(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazol-3-yl) ) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 5)
Compound 1 is obtained from Boc- (D) -Trp (10 mmol), naphthalen-1-yl-methanamine, 3- (1H-indol-3-yl) propane hydrazide and Boc-2-amino-2-methylpropanoic acid. Obtained in 33% overall yield after purification by HPLC, according to the general synthetic scheme.

Example 4:
(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 6)
Compound 6 was prepared from Boc- (D) -Trp (10 mmol), (3-methoxyphenyl) methanamine, 3- (1H-indol-3-yl) propane hydrazide and Boc-2-amino-2-methylpropanoic acid. Obtained in 25% overall yield after purification by HPLC, according to the general synthetic scheme.

Example 5:
(R) -N- (1- (4- (3-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 7)
Compound 7 is prepared from Boc- (D) -Trp (10 mmol), (3-methoxyphenyl) -methanamine, 2-phenylacetohydrazide and Boc-2-amino-2-methylpropanoic acid according to the general synthetic scheme. , Obtained in 30% overall yield after purification by HPLC.

Example 6:
(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 8)
Compound 8 can be synthesized from Boc- (D) -Trp (10 mmol), phenylmethanamine, 3- (1H-indol-3-yl) propanehydrazide and Boc-2-amino-2-methylpropanoic acid. According to the synthesis scheme, 45% overall yield was obtained after purification by HPLC.

Example 7:
(R) -N- (1- (5- (3- (1H-Indol-3-yl) propyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 9)
Compound 9 is prepared from Boc- (D) -Trp (10 mmol), phenylmethanamine, 4- (1H-indol-3-yl) butanehydrazide and Boc-2-amino-2-methylpropanoic acid According to the synthesis scheme, it was obtained in 38% overall yield after purification by HPLC.

Example 8:
(R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 10)
Compound 10 was prepared from Boc- (D) -Trp (10 mmol), (3-methoxyphenyl) methanamine, 4- (1H-indol-3-yl) butanehydrazide and Boc-2-amino-2-methylpropanoic acid. Obtained in 25% overall yield after purification by HPLC, according to the general synthetic scheme.

Example 9:
(R) -N- (1- (5- (3- (1H-Indol-3-yl) propyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 11)
Compound 11 is made from Boc- (D) -Trp (10 mmol), naphthalen-1-ylmethanamine, 4- (1H-indol-3-yl) butanehydrazide and Boc-2-amino-2-methylpropanoic acid. Obtained in 22% overall yield after purification by HPLC, according to the general synthetic scheme.

Example 10:
(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 12)
Compound 12 is derived from Boc- (D) -Trp (10 mmol), (4-methoxyphenyl) methanamine, 3- (1H-indol-3-yl) propane hydrazide and Boc-2-amino-2-methylpropanoic acid. Obtained in 28% overall yield after purification by HPLC, according to the general synthetic scheme.

Example 11:
(R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 13)
Compound 13 is prepared from Boc- (D) -Trp (10 mmol), (4-methoxyphenyl) -methanamine, 2-phenylacetohydrazide and Boc-2-amino-2-methylpropanoic acid according to the general synthetic scheme. , Obtained in 37% overall yield after purification by HPLC.

Example 12:
(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 15)
Compound 15 was synthesized from Boc- (D) -Trp (10 mmol), hexane-1-amine, 3- (1H-indol-3-yl) propane hydrazide and Boc-2-amino-2-methylpropanoic acid. According to the general synthetic scheme, 28% overall yield was obtained after purification by HPLC.

Example 13:
(S) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 18)
Compound 18 consists of Boc- (L) -Trp (10 mmol), (2,4-dimethoxyphenyl) methanamine, 3- (1H-indol-3-yl) propane hydrazide and Boc-2-amino-2-methylpropane. Obtained from the acid in 30% overall yield after purification by HPLC according to the general synthetic scheme.

Example 14:
(R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 23)
Compound 23 is obtained from Boc- (D) -Trp (10 mmol), (4-methoxyphenyl) methanamine, 4- (1H-indol-3-yl) butanehydrazide and Boc-2-amino-2-methylpropanoic acid. Obtained in 25% overall yield after purification by HPLC, according to the general synthetic scheme.

Example 15:
(R) -N- (1- (5- (2- (1H-Indol-3-yl) ethyl) -4- (2-methoxy) benzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 25)
Compound 25 was prepared from Boc- (D) -Trp (10 mmol), (2-methoxyphenyl) methanamine, 3- (1H-indol-3-yl) propane hydrazide and Boc-2-amino-2-methylpropanoic acid. Obtained in 28% overall yield after purification by HPLC, according to the general synthetic scheme.

Data for further exemplary embodiments synthesized according to a general synthetic scheme are summarized below (see also Table 1):
(R) -N- (1- (5- (3- (1H-Indol-3-yl) propyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 3):

(R) -N- (1- (5- (3- (1H-Indol-3-yl) propyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 16):

(R) -N- (1- (4,5-bis (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 17):

(R) -N- (1- (4- (3-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 19):

(R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 20):

(R) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole- 3-yl) ethyl) -2-amino-2-methylpropanamide (compound 22):

(R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5- (3- (1H-indol-3-yl) propyl) -4H-1,2, 4-Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 24):

(R) -N- (1- (4- (2-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 26):

(R) -N- (2- (1H-indol-3-yl) -1- (4- (naphthalen-1-ylmethyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) Ethyl) -2-amino-2-methylpropanamide (Compound 27):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3,4-dichlorobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 28):

(R) -N- (1- (4- (4-Fluorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 30):

(R) -N- (1- (4- (4-Methylbenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole- 3-yl) ethyl) -2-amino-2-methylpropanamide (compound 33):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methylbenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 34):

(R) -N- (1- (4- (4-methylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 37):

(R) -N- (1- (5-Benzyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) -2-amino-2-methylpropanamide (Compound 39):

(R) -N- (1- (4- (4-Ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 43):

(R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) Piperidine-4-carboxamide (Compound 44):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-Indol-3-yl) ethyl) piperidine-4-carboxamide (Compound 45):

(R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Aminoacetamide (Compound 50):

(R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2- (Pyridin-2-yl) acetamide (Compound 51):

(R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) picolinamide (Compound 64):

(R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) pyrazine-2-carboxamide (Compound 66):

(S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide (Compound 70):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) pyrazine-2-carboxamide (Compound 71):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) picolinamide (Compound 73):

(R) -1- (5- (2- (1H-Indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl)- 2- (1H-Indol-3-yl) ethanamine (Compound 74):

(R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) Picolinamide (Compound 79):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-Indol-3-yl) ethyl) picolinamide (Compound 80):

(R) -N-1- (5- (2- (1H-Indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl)- 2- (1H-Indol-3-yl) ethyl) piperazine-2-carboxamide (Compound 81):

(S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide (Compound 89):

(R) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide (Compound 90):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-bromobenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 92):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2-Phenylethyl) -2-amino-2-methylpropanamide (Compound 93):

(R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide (compound 95):

(R) -N- (1- (5-((1H-Indol-3-yl) methyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 96):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 97):

(R) -N- (1- (5-((1H-indol-3-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 98):

(R) -N- (1- (5-((1H-indol-3-yl) methyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 99):

(R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 102):

(R) -N- (1- (5-((1H-Indol-3-yl) methyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2 -(1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 101):

(R) -N- (1- (5-((1H-Indol-3-yl) methyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide (compound 104):

(R) -N- (1- (5-Benzyl-4- (2,2-diphenylethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 106):

(R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,2-diphenylethyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 107):

(R) -N- (1- (4,5-dibenzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2 -Methylpropanamide (Compound 109):

(R) -N- (1- (5-Benzyl-4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino -2-Methylpropanamide (Compound 110):

(R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (compound 111):

(S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 112):

(R) -N- (1- (4- (3,5-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 113):

(R) -N- (1- (4- (4-Bromobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 114):

(R) -N- (1- (4- (2-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 115):

(S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 116):

(R) -N- (1- (4,5-diphenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2 -Methylpropanamide (Compound 117):

(R) -N- (1- (4- (3,4-dichlorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 118):

(R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2-phenylethyl) -2-amino-2- Methylpropanamide (Compound 120):

(R) -N- (1- (4- (4-Fluorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 121):

(R) -N- (1- (4- (3,4-dichlorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 122):

(R) -N- (1- (4- (4-methylbenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 124):

(S) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole- 3-yl) ethyl) -2-amino-2-methylpropanamide (compound 125):

(S) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 126):

N-((R) -1- (4- (4-nitrobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 128):

(S) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 129):

(R) -N- (1- (4- (4-methoxyphenethyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -2-Amino-2-methylpropanamide (Compound 130)

(R) -N- (2- (1H-Indol-3-yl) -1- (5-phenethyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazol-3-yl) Ethyl) -2-amino-2-methylpropanamide (Compound 132):

N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide (Compound 179):

N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl ) -Tetrahydro-2H-pyran-4-carboxamide (Compound 184):

N-((R) -1- (5-((1H-indol-3-yl) methyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2 -(1H-Indol-3-yl) ethyl) -2-amino-2-methylpropanamide (Compound 185):

TABLE 1 Further exemplary embodiments and synthetic procedures and MS data (compound numbers 2, 3, 14, 16, 17, 19-22, 24, 26-35, 36-122, 124-126, 128- 150, 152-190):

II) GHS-R1a receptor-ligand binding assay (membrane preparation from transfected LLC PK-1 cells)
GHS-R1a receptor binding / affinity studies were performed according to Guerlavais et al. (J. Med. Chem. 2003, 46: 1191-1203).

LLC PK-1 cells (ECACC No. 86121112) of the renal epithelial cell line derived from porcine kidney, with human GHS-R1a cDNA (Guerlavais et al., J. Med. Chem. 2003, 46: 1191-1203) Plasma membranes (10 μg protein) isolated from transiently transfected cells were mixed with homogenization buffer HB [50 mM Tris (pH 7.3), 5 mM MgCl ₂ , 2.5 mM EDTA and 30 μg / mL. Of bacitracin (Sigma)] at 25 ° C. (steady conditions) for 60 minutes with 60 pM ¹²⁵ I-His ⁹ -ghrelin (Amersham) in the presence or absence of competing compounds (compounds of the invention). Incubated with.

The binding affinity of each compound to be tested for human GHS-R1a was measured by increasing the concentration of the test compound (10 ⁻¹¹ M to 10 ⁻² M) by displacement of radiolabeled ghrelin (each test Were performed in triplicate).

Non-specific binding was defined using excess (10 ⁻⁶ M) ghrelin. For the binding reaction, 4 mL of ice-cold HB was added, followed by a Whatman GP / C filter (presoaked with 0.5% polyethyleneimine to avoid excess radioligand binding to this filter). And stopped by rapid filtration. Filter, ice-cold wash buffer 3mL washed 3 times with [tris (pH 7.3) of 50 mM, MgCl ₂ of 10 mM, X-100 Triton EDTA and 0.015% of 2.5mM (w / v)] And the radioactivity bound to the membrane was measured in a gamma counter (Kontron Analytical Gamma Magic, automatic gamma counting system).

The concentration of test compound required to inhibit radiolabeled ghrelin binding by 50% (IC ₅₀ ) was defined by fitting an antagonistic binding curve using non-linear regression.

In Table 2 below, the results obtained for selected compounds of the present invention are presented in comparison with prior art examples. The IC ₅₀ values shown are the average of at least two independent tests performed in triplicate tests.

FIGS. 1-13 show GHS− with ¹²⁵ I-His ⁹ -ghrelin and selected compounds ⁹ , 31, 39, 45, 50, 62, 64, 71, 73, 74, 79, 81 and 90. FIG. 6 shows measured competition plots of R1a receptor ligand binding assay.

Table 2: GHS-R1a receptor-ligand binding assay test results (IC ₅₀ values for some selected exemplary compounds)

III) In vitro intracellular calcium release assay using CHO transfected with human GHS-R1a The ability of the compounds of the present invention to modulate GHS receptor activity has been demonstrated in CHO cells transfected with human GHS-R1a. Was evaluated by an in vitro intracellular calcium release assay.

  Intracellular calcium release or its inhibition was measured using a fluorescent calcium indicator assay (FLIPR) and Fluo-4 AM.

  CHO cells (CHO-KI Chinese hamster ovary cell line, ATCC number CCL-61) were transiently transfected with human GHS-R1a by electroporation and in 96-well black bottom plates (Corning 3603) (80000 cells / well). Transient transfection was performed using the Easy Optima Electroporator (Equibio) according to the manufacturer's instructions.

Transfected cells were treated with Dulbecco's modified Eagle's medium without phenol red, 10% (v / v) nonessential amino acids, 2 nM glutamine and streptomycin-penicillin (250 μg-250 u / ml) (all from Cambrex). Grown in supplemented medium at 37 ° C. in a humidified atmosphere of 5% CO ₂ for 24 hours.

After incubation, the transfected cells were treated with 150 μl of Buffer A [Hanks Balanced Salt Solution (Sigma H-6648), 0.5% (v / v) BSA (Sigma A7906), 20 mM CaCl ₂ , 2.5 mM. Of probenecid (pH 7.4, dissolved in 1M NaOH) (Sigma P-8761)] and then the fluorescent calcium indicator Fluo-4 AM (10 ⁻⁶ M) prepared in buffer A (Interchim UP72972) ) And 0.06% pluronic acid (Molecular probes P-6867) (moderate ionic surfactant to facilitate Fluo-4AM ester loading) (loading: 120 μl / ml per well) A bath containing pluronic acid and 1 μM Fluo-4AM Fur A100myueru, was loaded with those containing was added to the cells).

  After loading with Fluo-4AM, the transfected cells were incubated for 1 hour at 37 ° C. in the dark.

The compound to be tested was dissolved in buffer A at a concentration of 10 ⁻⁶ M in triplicate and dispensed into another 96 well plate (Fisher Labosi A1210500).

  After incubation, excess Fluo-4AM was removed, 100 μl of Buffer A was added to each well at room temperature and immediately removed by aspiration. This was then repeated before 50 μl of buffer A was added to each well.

  Transfected cells were further incubated at room temperature for 30 minutes to complete intracellular de-esterification of Fluo-4AM ester.

  Subsequently, both plates, ie the black bottom plate containing the transfected cells and the microtiter plate containing the compound to be tested, are then temperature-controlled (25 ° C.) for fluorescence output measurement. Placed in a FlexStation instrument (benchtop scanning fluorimeter FlexStation II, Molecular Devices, Sunnyvale, California, USA).

  Since Fluo-4AM shows a large increase in fluorescence intensity in response to calcium binding, the fluorescence output can be used directly as a proportional measure of intracellular calcium release.

  Basal fluorescence output from the transfected cells was measured for 15 seconds and then 50 μl of the compound to be tested was automatically dispensed into the wells containing the transfected cells. The fluorescence output was then recorded over an additional 45 seconds.

The excitation wavelength and emission wavelength were 485 nm and 525 nm, respectively. The basal fluorescence intensity of transfected cells loaded with Fluo-4AM without the compound to be tested varied in any unit between 800 and 1200, but was dye-loaded after incubation with the compound to be tested. The maximum fluorescence output of transfected cells varied in arbitrary units from 5000 to 7000, which is equivalent to that achieved by stimulation of dye-loaded transfected cells with 10 ⁻⁶ M ghrelin. Met.

  For each compound to be tested, the change in fluorescence output after addition of each compound was compared to the basal fluorescence output measured by adding only 50 μl of buffer A to the negative control, ie transfected cells.

  The ability and extent of each compound to be tested to cause calcium release was measured against the basal level (0%) and the maximum level achieved with 1 μM ghrelin (100%).

For compounds to be tested identified as GHS receptor agonists, EC ₅₀ and KI values were measured using dose-response curves.

As for the compounds to be tested identified as GHS receptor antagonists, IC ₅₀ and Kb (antagonist dissociation constant) values were used using an antagonist inhibition curve in the presence of 10 ⁻⁷ M (submaximal concentration) ghrelin. Measured. IC ₅₀ values were calculated as the molar concentration of GHS receptor antagonist that reduces the maximal response of ghrelin by 50%. Kb values were estimated using the Cheng-Prusoff equation (Lazareno S and Birdsall NJ, Trends Pharmacol Sci. 1993, 14 (6): 237-239).

FIGS. 14-40 show compounds 1, 9, 12, 20, 22, 31, 39, 41, 42, 45, 46, 47, 48, 49, 50, 51, 55, 62, 64, 67, 71, 73. 74, 79, 81, 90 and ghrelin, calculated dose-response plots of in vitro intracellular calcium release assay using human GHS-R1a transfected CHO cells and EC ₅₀ for agonist compounds and IC ₅₀ and Kb for KI values and antagonist compounds are shown.

IV) Assay of in vivo GH concentration in the plasma of male rats By evaluating the GH plasma concentration in male rats, the modulatory action (antagonist action or agonist action) of the compound of the present invention which is a GHS receptor analog ligand. ).

  In principle, in vivo GH concentrations in rat plasma were assayed according to Torsello et al. (Eur. J. Pharmacol. 1998, 360: 123-129).

  Male Sprague-Dawley pups (Charles River, Caico, Italy) were isolated from their mothers at 7 days of age and randomly redistributed into pens, thus each having 10-12 pups. Brought up. On the 10th day after birth, the pups were again isolated from their mothers.

  The compound to be tested was dissolved in a solvent [DMSO (0.4% of total volume), distilled water (4% of total volume), final volume with saline].

  One hour after isolation from their mothers, pups were given an equal volume of compound to be tested (160 μg / kg body weight, subcutaneous) at −10 minutes, then hexarelin (1 kg body weight) at 0 minutes. 80 μg per dose (subcutaneous) or vehicle and then sacrificed 15 minutes by decapitation. Trunk blood was collected, immediately centrifuged, and plasma samples were stored at −20 ° C. until assayed for determination of GH concentration.

  Plasma GH concentrations were measured using a rat growth hormone enzyme immunoassay kit (SPIbio, France, catalog number 589601) according to the manufacturer's instructions. Values are expressed as ng / mL (plasma) with respect to the NIDDK rat-GH-RP2 standard (titer IU / mg).

  The limit of detection calculated as the concentration resulting in 15% displacement of the initial tracer is 0.5 ng / ml and the intra-assay and inter-assay coefficients of variability are 4% (n = 24) and 14% (n = 9).

  In Table 3 below, the results obtained for selected compounds of the invention are presented.

Table 3: Relative GH concentrations in rat plasma after treatment with selected compounds of the invention (160 μg / kg body weight, subcutaneous) and / or hexarelin (80 μg / kg body weight, subcutaneous) and / or vehicle

V) Assay of feeding behavior (feeding) of male rats in the early adult period The effect of the compound of the present invention, which is a GHS receptor analog ligand, on the feeding behavior of male rats in the early adult period, ie, the effect on feeding was assayed. .

  In principle, the feeding behavior (feeding) assay of early adult male rats was performed according to Torsello et al. (Eur. J. Pharmacol. 1998, 360: 123-129).

  For the assay, early adult rats weighing 200-250 g (Charles River, Caico, Italy) were used.

  Rats were acclimated for one week in individual home cages and placed in animal room conditions (22 ± 2 ° C., 65% humidity, artificial light duration 08.00 to 20.00). The next week, the rats were trained for a day to mimic the experimental procedure. Rats were kept free to reach dry pellets and tap water throughout the entire experimental period. At the end of the training, the rats to be tested (10.00-11.00 am) are tested subcutaneously (160 μg / kg body weight) and / or hexarelin (80 μg / kg body weight) and / or vehicle [DMSO (total 0.4% of volume), distilled water (4% of total volume), final volume with saline].

  Hexarelin was used to investigate the effect of the compounds to be tested on the stimulated feeding behavior. Immediately after injection, animals were returned to their home cages containing known amounts of standard rat chow and, optionally, water. Every hour for the next 6 hours, the remaining food was carefully collected and weighed to the nearest 0.1 g. Feeding was normalized for rat body weight and expressed as grams of food consumed per 100 grams of rat body weight.

  In Table 4 below, the results obtained for selected compounds of the present invention are presented.

Table 4: Adults after 2 hours, 6 hours and after treatment with selected compounds according to the invention (160 μg / kg body weight, subcutaneous) and / or hexarelin (80 μg / kg body weight, subcutaneous) and / or vehicle Cumulative food intake of initial rats (g of food per 100 g of body weight)

VI) Motilin receptor-ligand binding assay (using human recombinant HEK-293 cells)
Motilin receptor binding / affinity studies were performed as described by Feigner SD et al. (Science 1999, 284: 2184-2188). The assay was performed under the following conditions:
Origin: Human recombinant HEK-293 cells [Motilin-Receptor 1a (MTL-R1a)]
Ligand: 0.1 nM [ ¹²⁵ I] motilin (human, porcine)
Vehicle: 1% DMSO
Incubation time / temperature: 2.5 hours (25 ° C.)
Incubation buffer: 50 mM Tris (pH 7.4), 10 mM MgCl ₂ , 0.5% BSA
Non-specific ligand: 1 μM motilin (human, pig)
The compounds of the invention were tested at concentrations including 0.01 μM, 0.1 μM, 1 μM and 10 μM.

IC ₅₀ values were measured by non-linear least squares regression using a Data Analysis Toolbox (MDL Information Systems, USA).

  In Table 5 below, the results obtained for selected compounds of the present invention are presented.

Table 5: Test results of the motilin receptor-ligand binding assay (IC ₅₀ values for some selected exemplary substances)

VII) Study of anti-cachexia effect in an adjuvant-induced arthritis model system The efficacy of the compounds of the invention in the treatment of cachexia was determined according to Ibanez de Caceres I et al. And a cachexia model system (Roubenoff R et al., Arthritis Rheum. 1997, 40 (3): 534-539).

  Table 6 shows the anti-cachexia effect of Compound 44 (0.1 μg / kg / day, subcutaneous injection) in arthritic rats compared to adjuvant-induced arthritis without medical treatment.

Table 6: Weight change in grams (average of 6 animals per group)

VIII) Study of the anti-inhibitory effect of isoproterol-induced lipolysis in an adipocyte model The efficacy of the compounds of the present invention in the inhibition of isoproterol-induced lipolysis induced by unacylated ghrelin Investigated using an adipocyte model.

Isolation of primary mouse adipocytes Mice were fed a high fat diet (60% lipid) to induce obesity for 12 and 18 weeks starting at 4 weeks of age.

White adipose tissue from epididymal fat is minced and Krebs-Ringer-bicarbonate-Hepes (KRBH) buffer (20 mM Hepes (pH 7.4), 120 mM NaCl, 4.7 mM KCl, 1.2 mM K ₂ HPO ₄ , 2.5 mM CaCl ₂ , 1.2 mM MgSO ₄ , 24 mM NaHCO ₃ ) saturated with CO ₂ , glucose (1 mg / mL), 1% BSA and collagenase (2 mg / g tissue) ). Digestion was performed at 37 ° C. for 45 minutes under constant shaking (250 rpm).

  The cell suspension was filtered through a nylon mesh to separate adipocytes and tissue fragments and washed 3 times in 3 mL warm KRBH 1% BSA.

  Cells were resuspended in KRBH 1% BSA and incubated for 30 minutes at 37 ° C. in a shaker (75 rpm).

Lipolysis Assay Lipolysis in primary adipocytes was induced at 37 ° C. with constant (125 rpm) shaking for 90 minutes with 30 nM isoproterenol in KRBH 4% BSA.

  Lipolysis in differentiated cells was induced with 30 nM isoproterenol in the absence of DMEM FBS at 90 ° C. for 90 minutes with shaking every 15 minutes.

The inhibitory effect of unacylated ghrelin (UAG) on isoproterenol-induced lipolysis was selected at 10 ⁻⁷ M with increasing UAG concentrations from 10 ⁻¹¹ M to 10 ⁻⁶ M Recorded in the presence or absence of compound.

  The lipolysis index was evaluated by measuring glycerol release after triglyceride hydrolysis.

Antagonism was measured as follows:

  Figures 41-46 show selected compounds 9, 38 against inhibition curves of unacylated ghrelin (UAG) isoprorelenol-induced lipolysis in primary adipocytes from mice with diet-induced obesity. , 50, 64, 74, 81 are shown.

FIG. 1 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 9 of the Examples section. FIG. 2 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 31 of the Examples section. FIG. 3 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 39 of the Examples section. FIG. 4 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 45 of the Examples section. FIG. 5 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 50 of the Examples section. FIG. 6 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 62 of the Examples section. FIG. 7 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 64 of the Examples section. FIG. 8 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 71 of the Examples section. FIG. 9 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 73 of the Examples section. FIG. 10 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 74 of the Examples section. FIG. 11 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 79 of the Examples section. FIG. 12 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 81 of the Example section. FIG. 13 shows the measured competition plot of the GHS-R1a receptor ligand binding assay with ¹²⁵ I-His ⁹ -ghrelin and selected compound 90 of the Examples section. FIG. 14 shows the calculated dose-response of an in vitro intracellular calcium release assay for selected compounds 1 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 15 shows the calculated dose-response of an in vitro intracellular calcium release assay for selected compounds 9 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 16 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 12 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 17 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 20 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 18 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 22 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 19 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 31 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 20 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 39 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 21 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 41 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 22 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 42 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 23 shows the calculated dose-response of an in vitro intracellular calcium release assay for selected compounds 45 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 24 shows the calculated dose-response of an in vitro intracellular calcium release assay for selected compounds 46 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 25 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 47 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 26 shows the calculated dose-response of the in vitro intracellular calcium release assay of selected compounds 48 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 27 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 49 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 28 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 50 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 29 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 51 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 30 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 55 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 31 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 62 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 32 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 64 described in Example III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 33 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 67 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 34 shows the calculated dose-response of an in vitro intracellular calcium release assay for selected compounds 71 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 35 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 73 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 36 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 74 described in Example Part III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 37 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 79 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 38 shows the calculated dose-response of an in vitro intracellular calcium release assay for selected compounds 81 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 39 shows the calculated dose-response of an in vitro intracellular calcium release assay of selected compounds 90 described in Example section III) using human GHS-R1a transfected CHO cells. Plots and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 40 shows calculated dose-response plots of ghrelin in vitro calcium release assay in vitro using human GHS-R1a transfected CHO cells and EC ₅₀ and KI values for GHS receptor agonists and IC ₅₀ and Kb for GHS receptor antagonists are shown. FIG. 41 is an inhibition curve of unacylated ghrelin (UAG) isoprorerenol-induced lipolysis in primary adipocytes from mice with diet-induced obesity, as described in Examples VIII). 2 shows the effect of selected compound 9 on FIG. 42 is an inhibition curve of unacylated ghrelin (UAG) isoprorelenol-induced lipolysis in primary adipocytes from mice with diet-induced obesity, as described in Examples VIII). 2 shows the effect of selected compound 38 on FIG. 43 is an inhibition curve of unacylated ghrelin (UAG) isoprorelenol-induced lipolysis in primary adipocytes from mice with diet-induced obesity, as described in Examples VIII). 2 shows the effect of selected compound 50 on FIG. 44 is an inhibition curve of unacylated ghrelin (UAG) isoprorelenol-induced lipolysis in primary adipocytes from mice with diet-induced obesity, as described in Examples VIII). 2 shows the effect of selected compound 64 on FIG. 45 is an inhibition curve of unacylated ghrelin (UAG) isoprorelenol-induced lipolysis in primary adipocytes from mice with diet-induced obesity as described in Examples VIII). 2 shows the effect of selected compound 74 on FIG. 46 is an inhibition curve of unacylated ghrelin (UAG) isoprorerenol-induced lipolysis in primary adipocytes from mice with diet-induced obesity, as described in Examples VIII). 2 shows the effect of selected compound 81 on

Claims (26)

Formula (I)

[Where:
R1 and R2 are independently of each other “a hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, aryl. Selected from the group consisting of "alkylsulfonyl", which is optionally alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups with "halogen,- F, -Cl, -Br, -I, -N 3, -CN, -NR7R8, -OH, -NO 2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl , -O-arylalkyl "substituted by up to three substituents independently selected from the group consisting of" alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl " Are optionally selected from “halogen, —F, —Cl, —Br, —I, —N ₃ , —CN, —NR 7 R 8, —OH, —NO ₂ , alkyl, aryl, arylalkyl, — Substituted with up to three substituents independently selected from the group consisting of “O-alkyl, —O-aryl, —O-arylalkyl”;
One of the groups R3 and R4 is a hydrogen atom, while the other group is "hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl,- Alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO- Arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, -alkyl-CO-heterocyclylalkyl, -alkyl-C (O) O-aryl, -alkyl-C (O) O-Aryl A Alkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O-heterocyclyl, -alkyl-C (O) O-heterocyclylalkyl, - alkyl -CO-NH _2, - alkyl -CO-OH, - alkyl -NH _2, - alkyl _{-NH-C (NH) -NH 2} , alkylsulfonyl, arylsulfonyl, aryl-alkylsulfonyl, alkyl -S- alkyl, Selected from the group consisting of “alkyl-S—H”, optionally in aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups, “halogen, —F, —Cl, — _{br, -I, -N 3, -CN} , -NR7R8, -OH, -NO 2, alkylenediamines , Aryl, arylalkyl, —O-alkyl, —O-aryl, —O-arylalkyl ”, preferably substituted with up to three substituents independently selected from the group consisting of“ arylalkyl, Heteroarylalkyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O- Heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl,- Alkyl-C (O O-aryl, -alkyl-C (O) O-arylalkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O- heterocyclyl, - alkyl -C (O) O-heterocyclylalkyl, - alkyl -CO-NH _2, - alkyl -CO-OH, - alkyl -NH _2, - consisting of alkyl _{-NH-C (NH) -NH 2} " Selected from the group, optionally in the aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and / or heterocyclylalkyl groups, “halogen, —F, —Cl, —Br, —I, —N ₃ , -CN, -NR7R8, -OH, -NO _2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl , -O-arylalkyl "substituted by up to 3 substituents independently selected from the group consisting of:
R5 represents “hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —CO-alkyl, —CO-cycloalkyl, —CO-cycloalkylalkyl. , -CO- aryl, -CO- arylalkyl, -CO- heteroaryl, -CO- heteroarylalkyl, -CO- heterocyclyl, -CO- ^{heterocyclylalkyl, -CO-C * (R9R10)} -NH 2, -CO —CH ₂ —C ^* (R 9 R 10) —NH ₂ , —CO—C ^* (R 9 R 10) —CH ₂ —NH ₂ , alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl ”, which are optionally "Halogen, -F, -Cl, _{Br, -I, -N 3, -CN} , -NR7R8, -OH, -NO 2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl, independently from the group consisting of -O- arylalkyl " Is preferably substituted by up to three substituents selected from: "hydrogen atom, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-aryl alkyl, -CO- heteroarylalkyl, -CO- ^{heterocyclyl, -CO-C * (R9R10)} -NH 2, -CO-CH 2 -C * (R9R10) -NH 2, -CO-C * (R9R10) - "is selected from the group consisting of, they can optionally," CH ₂ -NH ₂ halogen, -F, -Cl, -Br, -I , -N 3, -CN, -NR7R8, -OH, -NO 2 Alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl, which is substituted by up to three substituents selected independently from the group consisting of -O- arylalkyl ";
R6 is selected from the group consisting of "hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl", preferably a hydrogen atom;
R7 and R8, independently of one another, are selected from the group consisting of “hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl”, preferably a hydrogen atom;
R9 and R10 are independently selected from the group consisting of “hydrogen atom, alkyl, neutral α-amino acid side chain, non-neutral α-amino acid side chain”, preferably “hydrogen atom, alkyl Selected from the group consisting of;
m is 0, 1 or 2, preferably 0; and
^* Means a carbon atom in the R or S configuration when chiral] is a physiological and / or pathophysiological condition in mammals mediated by the GHS receptor. Use for the manufacture of a medicament for the treatment or prevention of Use of a compound of formula (I) according to claim 1, wherein
R3 represents "-alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl, -Alkyl-C (O) O-aryl, -alkyl-C (O) O-arylalkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl -C (O) O-heterocyclyl, - alkyl -C (O) O-heterocyclylalkyl, - alkyl -CO-NH _2, - alkyl -CO-OH, - alkyl _{-NH-C (NH) -NH 2} , alkyl -S-alkyl, alkyl-SH ", preferably" -alkyl-CO-aryl " Kill, - alkyl -C (O) O-arylalkyl, - alkyl -CO-NH _2, - use is selected from the group consisting of alkyl -CO-OH ". Use of a compound of formula (I) according to claim 1, wherein
R4 is a hydrogen atom;
R5 represents "hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, -CO-cycloalkyl,- Selected from the group consisting of "CO-cycloalkylalkyl, -CO-aryl, -CO-arylalkyl, -CO-heteroaryl, -CO-heteroarylalkyl, -CO-heterocyclyl, -CO-heterocyclylalkyl" However,
If R5 is "-CO-heteroarylalkyl" then "heteroaryl" is not an imidazole and R5 is "-CO-heterocyclyl" and "heterocyclyl" contains only nitrogen atoms as heteroatoms For example, if "heterocyclyl" contains at least two nitrogen atoms and R5 is "-CO-heterocyclylalkyl" and "heterocyclyl" contains only nitrogen atoms as heteroatoms, then "heterocyclyl" “When 1 or 2 nitrogen atoms are contained, the nitrogen atom is located at the 1-position of“ heterocyclyl ”which is an atom that directly bonds“ heterocyclyl ”and carbonyl group“ —CO— ”. Not located;
"Alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, -CO-cycloalkyl, -CO-cycloalkylalkyl, “—CO-aryl, —CO-reelalkyl, —CO-heteroaryl, —CO-heteroarylalkyl, —CO-heterocyclyl and / or —CO-heterocyclylalkyl” are sometimes referred to as “halogen, —F, —Cl _{, -Br, -I, -N 3,} -CN, -NR7R8, -OH, -NO 2, alkyl, aryl, arylalkyl, -O- alkyl, -O- aryl, the group consisting of -O- arylalkyl " Selected independently from Substituted with up to 3 substituents provided that
When R5 is "-CO-cycloalkyl" or "-CO-cycloalkylalkyl", R5 is "cycloalkyl" and when R5 is "-CO-cycloalkyl", the carbonyl group "-CO- In the case where “and” or R5 is “—CO-cycloalkylalkyl”, the cycloalkyl, which is a carbon atom directly bonding to “alkyl”, is not substituted with NR7R8 at the 1-position, and R5 If "is" -CO-aryl "or" -CO-arylalkyl "and" aryl "is phenyl / benzene and is only substituted with one substituent, this one substitution The group is not -NR7R8;
R6 is a hydrogen atom;
R7 and R8, independently of one another, are selected from the group consisting of “hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl”, preferably a hydrogen atom; and m is 0, 1 or 2; Use that is preferably zero. Use of a compound of formula (I) according to claim 1, wherein
R1 is "hydrogen, methyl, (2-methoxyphenyl) -methyl, (3-methoxyphenyl) -methyl, (4-methoxyphenyl) -methyl, (3-methoxyphenyl) -ethyl, (4-methoxyphenyl)" -Ethyl, phenyl, phenyl-methyl, phenyl-ethyl, (4-ethylphenyl) -methyl, (4-methylphenyl) -methyl, (4-fluorophenyl) -methyl, (4-bromophenyl) -methyl, ( 2,4-dimethoxyphenyl) -methyl, (3,5-dimethoxyphenyl) -methyl, 2,2-diphenyl-ethyl, naphthalin-1-yl-methyl, 1H-indol-3-yl-methyl, 2- ( 1H-indol-3-yl) -ethyl, 3- (1H-indol-3-yl) -propyl, 4-methyl-phenyl, 4-ethyl- Phenyl, n-hexyl, (3,4-dichlorophenyl) -methyl, (4-nitro-phenyl) -methyl, (pyridin-2-yl) -methyl, (pyridin-3-yl) -methyl, (pyridine-4) -Yl) -methyl, (thiophen-2-yl) -methyl, (thiophen-3-yl) -methyl, (furan-2-yl) -methyl, (furan-3-yl) -methyl "Selected;
R2 is “methyl, 1H-indol-3-yl-methyl, 2- (1H-indol-3-yl) -ethyl, 3- (1H-indol-3-yl) -propyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 2-methoxy-phenylmethyl, 3-methoxy-phenylmethyl, 4-methoxy-phenylmethyl, 2-methoxy-phenylethyl, 3-methoxy-phenylethyl, 4-methoxy -Selected from the group consisting of "phenylethyl";
R3 represents “hydrogen atom, methyl, propan-2-yl, 2-methyl-propan-1-yl, butan-2-yl, butan-1-yl, —CH ₂ —SH, — (CH ₂ ) ₂ —. S-CH _3, 1H-indol-3-yl - methyl, phenyl - methyl, 2-phenyl - ethyl, -CH ₂ -O-CH ₂ - phenyl, -CH ₂ -CO-CH ₂ - phenyl, - (CH _{2) 2} -CO-CH ₂ - phenyl, -CH ₂ -C (O) O- _{phenyl, - (CH 2) 2 -C} (O) O- phenyl, hydroxy - methyl, 1-hydroxy - ethane-1 _{yl, -CH 2 -CO-NH 2,} - (CH 2) 2 -CO-NH 2, (1- hydroxy - benzene-4-yl) - _{methyl, -CH 2 -CO-OH, -} (CH 2) _{2 -CO-OH, - (CH} 2) 4 -NH 2, (1H- imidazol-5 Yl) - _{methyl, - (CH 2) 3 -NH} -C (NH) -NH 2, - (CH 2) 3 -NH 2, - from (CH ₂₎ group consisting of ₃ -NH-CO-NH ₂ " Selected, preferably “1H-indol-3-yl-methyl, —CH ₂ —CO—CH ₂ -phenyl, — (CH ₂ ) ₂ —CO—CH ₂ -phenyl, —CH ₂ —C (O ) O-phenyl, — (CH ₂ ) ₂ —C (O) O-phenyl ”;
R4 is a hydrogen atom;
R5 is "hydrogen _{atom, -CO-CH 2 -NH 2 (} Gly _{residues), - CO-CH 2 -CH} 2 -NH 2 (β-Ala _{residue), - CO-CHCH 3 -NH} 2 (D -And / or L-α-Ala residue), -CO- (pyrrolidin-2-yl) (D- and / or L-Pro residue), 2-amino-2-carbonyl-propane (2-amino-) Isobutyric acid / Aib residue), 4-carbonyl-1H-piperidine, 3-carbonyl-1H-piperidine, R- (3-carbonyl-1H-piperidine), S- (3-carbonyl-1H-piperidine), 2- Carbonyl-1H-piperidine, R- (2-carbonyl-1H-piperidine), S- (2-carbonyl-1H-piperidine), 1-amino-2-carbonyl-benzene, carbonyl-cyclohexane, 2-acetyl-pyridy 3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine, 4-propionyl-pyridine, (R-1-amino) -2-carbonyl-cyclohexane, (S-1- Amino) -2-carbonyl-cyclohexane, 2-carbonyl-1H-imidazole, 2-carbonyl-pyridine, 3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-amino-3-carbonyl-pyridine, 2-carbonyl-pyrazine 2-carbonyl-4-hydroxy-1H-pyrrolidine, 4-carbonyl-1H, 3H-diazacyclohexane, methylsulfonyl, phenylsulfonyl, 1-carbonyl-1-amino-2-phenylethane, phenylmethyl, 1-carbonyl -4-azido-benzene, 2-carbo Nyl-2,5-dihydro-1H-pyrrole, 2-carbonyl-piperazine, 2-carbonyl-1H-pyrrolidine, 2-aminoethane, carbonyl-benzene, 2-carbonyl-pyrazine, 3-carbonyl-pyrazine, 4-carbonyl- Selected from the group consisting of "oxacyclohexane, 4-methyl-phenylsulfonyl, phenylmethyl-sulfonyl";
Use wherein R6 is a hydrogen atom; and m is 0. Use of a compound of formula (I) according to claim 4, wherein
R3 _{is, "- CH 2 -CO-CH} 2 - _{phenyl, - (CH 2) 2 -CO} -CH 2 - _{phenyl, -CH 2 -CO-NH 2,} - (CH 2) 2 -CO-NH 2, _{-CH 2 -CO-OH, - (} CH 2) 2 -CO-OH, - (CH 2) 3 -NH-C (NH) -NH 2, -CH 2 -SH, - (CH 2) 2 -S use selected from the group consisting of -CH ₃ ". Use of a compound of formula (I) according to claim 4, wherein
R5 is “hydrogen atom, methylsulfonyl, phenylsulfonyl, carbonyl-cyclohexane, (R-1-amino) -2-carbonyl-cyclohexane, (S-1-amino) -2-carbonyl-cyclohexane, 2-carbonyl-pyridine. 3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-acetyl-pyridine, 3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine, 4-propionyl-pyridine, 2 Uses selected from the group consisting of “amino-3-carbonyl-pyridine, 2-carbonyl-1H-imidazole, 2-carbonyl-pyrazine, 4-carbonyl-1H, 3H-diazacyclohexane”. Use according to any one of claims 1 to 6, wherein the compound is
Compound 1 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 2 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 3 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 4 (R) -N- (1- (5-benzyl-4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 5 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 6 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 7 (R) -N- (1- (4- (3-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 8 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 9 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 10 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 11 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 12 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 13 (R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 14 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (4-bromobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 15 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 16 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 17 (R) -N- (1- (4,5-bis (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- ( 1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 18 (S) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 19 (R) -N- (1- (4- (3-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 20 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 21 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3,5-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 22 (R) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 23 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 24 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5- (3- (1H-indol-3-yl) propyl) -4H-1, 2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 25 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2-methoxy) benzyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 26 (R) -N- (1- (4- (2-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 27 (R) -N- (2- (1H-indol-3-yl) -1- (4- (naphthalen-1-ylmethyl) -5-phenethyl-4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 28 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3,4-dichlorobenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 29 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-fluorobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 30 (R) -N- (1- (4- (4-fluorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 31 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 32 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,
Compound 33 (R) -N- (1- (4- (4-methylbenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 34 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methylbenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 36 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-2-carboxamide,
Compound 37 (R) -N- (1- (4- (4-methylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 38 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminobenzamide,
Compound 39 (R) -N- (1- (5-benzyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 40 (2S, 4R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -4-hydroxypyrrolidine-2-carboxamide,
Compound 41 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,
Compound 42 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,
Compound 43 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 44 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) piperidine-4-carboxamide,
Compound 45 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 46 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 47 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 48 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,
Compound 49 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,
Compound 50 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminoacetamide,
Compound 51 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-2-yl) acetamide,
Compound 52 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-4-yl) acetamide,
Compound 53 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) cyclohexanecarboxamide,
Compound 54 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 55 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,
Compound 56 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -3-aminopropanamide,
Compound 57 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-aminopropanamide,
Compound 58 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-3-yl) acetamide,
Compound 59 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -3- (pyridin-3-yl) propanamide,
Compound 60 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 61 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 62 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) piperidine-4-carboxamide,
Compound 63 (R) -N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) piperidine-2-carboxamide,
Compound 64 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) picolinamide,
Compound 65 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) isonicotinamide,
Compound 66 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) pyrazine-2-carboxamide,
Compound 67 (R) -N-1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) piperazine-2-carboxamide,
Compound 68 (S) -N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 69 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,
Compound 70 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2, 4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 71 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) pyrazine-2-carboxamide,
Compound 72 (R) -N-1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) piperazine-2-carboxamide,
Compound 73 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 74 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) ethanamine,
Compound 75 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-aminoacetamide,
Compound 76 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) pyrazine-2-carboxamide,
Compound 77 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) isonicotinamide,
Compound 78 (R) -N-1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) piperazine-2-carboxamide,
Compound 79 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) picolinamide,
Compound 80 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 81 (R) -N-1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-Indol-3-yl) ethyl) piperazine-2-carboxamide,
Compound 82 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-2-yl) acetamide,
Compound 83 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) piperidine-4-carboxamide,
Compound 84 (R) -N-1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) piperazine-2-carboxamide,
Compound 85 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) pyrazine-2-carboxamide,
Compound 86 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-cis-aminocyclohexanecarboxamide,
Compound 87 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,
Compound 88 (R) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-2-carboxamide,
Compound 89 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 90 (R) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 91 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 92 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-bromobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 93 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2-phenylethyl) -2-amino-2-methylpropanamide,
Compound 94 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (thiophen-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) piperidine-4-carboxamide,
Compound 95 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 96 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 97 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 98 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 99 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 100 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-methyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 101 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 102 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 103 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 104 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 105 (R) -N- (1- (5-benzyl-4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,
Compound 106 (R) -N- (1- (5-benzyl-4- (2,2-diphenylethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 107 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,2-diphenylethyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 108 (R) -N- (1- (4- (3,5-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 109 (R) -N- (1- (4,5-dibenzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino -2-methylpropanamide,
Compound 110 (R) -N- (1- (5-benzyl-4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,
Compound 111 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 112 (S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 113 (R) -N- (1- (4- (3,5-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 114 (R) -N- (1- (4- (4-bromobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 115 (R) -N- (1- (4- (2-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 116 (S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 117 (R) -N- (1- (4,5-diphenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino -2-methylpropanamide,
Compound 118 (R) -N- (1- (4- (3,4-dichlorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 119 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) ethanamine,
Compound 120 (R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2-phenylethyl) -2-amino- 2-methylpropanamide,
Compound 121 (R) -N- (1- (4- (4-fluorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 122 (R) -N- (1- (4- (3,4-dichlorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 124 (R) -N- (1- (4- (4-methylbenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 125 (S) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 126 (S) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 128 N-((R) -1- (4- (4-nitrobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 129 (S) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 130 (R) -N- (1- (4- (4-methoxyphenethyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 131 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (thiophen-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 132 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 133 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) piperidine-3-carboxamide,
Compound 134 (S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 135 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminoacetamide,
Compound 136 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-4-yl) acetamide,
Compound 137 (2R) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,
Compound 138 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) picolinamide,
Compound 139 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminopyridine-3-carboxamide;
Compound 140 (2S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-aminopropanamide,
Compound 141 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) isonicotinamide,
Compound 142 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) piperidine- 4-carboxamide,
Compound 143 (2S) -N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) Ethyl) pyrrolidine-2-carboxamide,
Compound 144 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) -2 -Aminoacetamide,
Compound 145 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) -2 -(Pyridin-2-yl) acetamide,
Compound 146 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) picolinamide ,
Compound 147 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 148 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 149 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,
Compound 150 (2S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 152 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,
Compound 153 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-trans-aminocyclohexanecarboxamide,
Compound 154 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-3-yl) acetamide,
Compound 155 (3S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,
Compound 156 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminobenzamide,
Compound 157 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 158 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 159 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) picolinamide,
Compound 160 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3 -Yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 161 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) pyrazine-2-carboxamide,
Compound 162 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) -2-aminoacetamide,
Compound 163 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) piperidine-4-carboxamide,
Compound 164 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) picolinamide,
Compound 165 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-acetamide,
Compound 166 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-4-carboxamide,
Compound 167 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 168 N-((R) -1- (5- (4-methoxybenzyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 169 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) picolinamide,
Compound 170 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-acetamide,
Compound 171 (R) -benzyl-3- (2-aminoisobutyramide) -3- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1 , 2,4-triazol-3-yl) -propanoate,
Compound 172 N-((R) -1- (5-benzyl-4-((pyridin-3-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 173 N-((R) -1- (4-benzyl-5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,
Compound 174 N-((R) -2- (1H-indol-3-yl) -1- (4-methyl-5-phenethyl-4H-1,2,4-triazol-3-yl) ethyl) picolinamide ,
Compound 175 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 176 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) benzamide,
Compound 177 (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) -N-phenylmethanesulfonylamine,
Compound 178 (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) -N-tosyl ethanamine,
Compound 179 N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 180 N-1-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) ethane-1,2-diamine,
Compound 181 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 182 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) picolinamide,
Compound 183 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-4-carboxamide,
Compound 184 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -tetrahydro-2H-pyran-4-carboxamide;
Compound 185 N-((R) -1- (5-((1H-indol-3-yl) methyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 186 (2S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-3-phenylpropanamide,
Compound 187 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) -N-tosylethanamine,
Compound 188 N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -4-azidobenzamide,
Compound 189 N-benzyl- (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole- 3-yl) etanamin,
Compound 190 (2S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2,5-dihydro-1H-pyrrole-2-carboxamide,
Use selected from the group consisting of.   8. Use according to any one of claims 1 to 7, wherein the treatment is achieved by modulation of GHS receptors.   9. Use according to any one of claims 1 to 8, wherein the compound is a GHS receptor antagonist.   10. Use according to claim 9, wherein the GHS receptor antagonist is compound 1, 3, 12, 13, 14, 18, 20, 22, 23, 33, 36, 37, 38, 41, 46, 47, 48, 49, 50, 51, 52, 53, 57, 58, 59, 60, 61, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 82, 85, 86, 87, 88, 89, 90, 91, 93, 101, 102, 109, 114, 116, 119, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 150, 152, 153, 154, 156, 157, 159, 160, 161, 164, 171, 174, 176, 178, 179, 182, 184, 186, 188 and / or Use is selected from the group consisting of 190.   9. Use according to any one of claims 1 to 8, wherein the compound is a GHS receptor agonist.   The use according to claim 11, wherein the GHS receptor agonist is compound 2, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 17, 19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 39, 40, 42, 43, 44, 45, 54, 55, 56, 62, 67, 78, 81, 83, 84, 87, 92, 94, 99, 103, 104, 105, 106, 107, 108, 110, 111, 115, 117, 118, 121, 122, 124, 130, 131, 142, 155, 158, 163, 173, 175, 180, Use selected from the group consisting of 181, 183, 185 and / or 187.   13. Use according to any one of claims 1 to 12, wherein the mammal is "human, domestic animal, cow, domestic animal, pet, cow, sheep, pig, goat, horse, pony, donkey, hinny". Use, preferably selected from the group consisting of: mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouse.   14. Use according to any one of claims 1 to 13, wherein the GHS receptor is "GHS type 1 receptor, GHS-R1a, GHS-R1b, motilin receptor, motilin receptor 1a, neurotensin. Preferably selected from the group consisting of receptor, TRH receptor, GPR38 (FM1), GPR39 (FM2), FM3, GHS-R subtype, GHS binding site, cardiac GHS-R, breast GHS-R " Use selected from the group consisting of "GHS type 1 receptor, GHS-R1a, GHS-R1b", most advantageously GHS-R1a.   15. Use according to any one of claims 1 to 14, wherein the physiological and / or pathophysiological state is "acute fatigue syndrome and muscle degeneration after selective surgery, adipogenesis, adiposity" Aging, decreased thymic function, decreased aging function in elderly ("ARFD"), aging disease in domestic animals, Alzheimer's disease, anorexia (eg associated with cachexia or aging); anxiety, blood pressure (reduced) , Weight gain / loss, fracture repair (promotion), bone remodeling stimulation, cachexia and protein deficiency due to chronic diseases such as cancer or AIDS, cardiac dysfunction (eg valvular disease, myocardial infarction, cardiac hypertrophy or congestive) Related to heart failure), cardiomyopathy, stimulation of cartilage growth, catabolic disease related to pulmonary dysfunction and ventilation dependence, catabolic side effects of glucocorticoid, catabolic status of aging, central nervous system disease (anti Chronic dialysis, chronic fatigue syndrome (CFS), cognitive improvement (eg in dementia, Alzheimer's disease), concomitant fractures (eg bone extension), transplant-related complications, congestive heart failure ( Alone / in combination with a corticotropin-releasing factor antagonist), Crohn's disease and ulcerative colitis, Cushing syndrome, dementia, depression, short-term, moderate and / or long-term regulation of energy balance, short-term feeding behavior Moderate and / or long-term regulation (stimulation and / or inhibition), frailty (eg elderly humans), gastrectomy (ghrelin replacement therapy), gastric postoperative ileus, improved glycemic control, growth hormone in the elderly Release stimulation, growth hormone replacement in stressed patients, growth promotion in livestock, Prader-Willi syndrome and Turner Growth retardation associated with syndrome, growth retardation associated with Crohn's disease, growth retardation, hair / nail growth maintenance, hip fracture, hunger, hyperadrenocorticism, hyperinsulinism including islet cell disease, hypothermia, suppression Immunodeficiency in individuals with a reduced T4 / T8 cell ratio, improved immune response to vaccines, immune system stimulation in livestock, immune system stimulation, immunosuppression in immunosuppressed patients, inflammation or inflammatory effects, inflammatory bowel disease, Insulin resistance in the heart, insulin resistance in type 2 diabetes, NIDDM, diabetes, type 1 diabetes, insulin resistance including type 2 diabetes, intrauterine growth retardation, irritable bowel syndrome, lipodystrophy (eg, HIV-induced), metabolism Maintenance of homeostasis, increased milk production in livestock, increased muscle mass / muscle strength, improved muscle motility, improved muscle strength, Maintenance of muscle strength / function in older humans, muscle atrophy, musculoskeletal disorders (eg in the elderly), Noonan syndrome, obesity and growth retardation associated with obesity, osteoblast stimulation, osteochondral dysplasia, osteoporosis, ovulation induction (Adjuvant treatment), physiological short stature, including children with growth hormone deficiency, postoperative ileus, attenuation of protein catabolism after major surgery / trauma, increased protein kinase B activity, psychosocial disturbance, pulmonary dysfunction and ventilation dependence , Improvement of lung function, induction of pulsatile growth hormone release, recovery of burn patients and reduction of hospitalization (promotion) of burn patients, renal failure or renal dysfunction resulting from growth delay, maintenance of kidney homeostasis of debilitated elderly, muscle loss Schizophrenia, sensory function maintenance (eg hearing, vision, olfaction and taste), short bowel syndrome, short stature associated with chronic disease, skeletal dysplasia, skin thickness maintenance, Sleep disorders, improved sleep quality, thrombocytopenia, thymic stimulation, dental repair or growth, tumor cell proliferation, ventricular dysfunction or reperfusion event, weakness associated with AIDS, weakness associated with chronic liver disease, chronic Weakness associated with obstructive pulmonary disease (COPD), weakness associated with multiple sclerosis or other neurodegenerative diseases, secondary weakness to fractures, stimulation of wool growth in sheep, wound healing (promotion), delayed wound healing Use selected from the group consisting of:   16. Use according to claim 15, wherein the physiological and / or pathophysiological state is: "growth retardation, cachexia, short, medium and / or long term regulation of energy balance; feeding Short-, medium- and / or long-term regulation (stimulation and / or inhibition) of behavior; adipogenesis, adiposity and / or obesity; weight gain and / or decline; diabetes, type 1 diabetes, type 2 diabetes, Use selected from the group consisting of: tumor cell proliferation; inflammation, inflammatory effects, postoperative ileus of the stomach, postoperative ileus and / or gastrectomy (ghrelin replacement therapy).   Use according to any one of claims 1 to 16, wherein the medicament contains at least one additional pharmacologically active substance.   18. Use according to claim 17, wherein such medicament comprises a GHS receptor antagonist and an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, most preferably rimonabant [1H-pyrazole-3-carboxamide, 5 Use of-(4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N-1-piperidinyl-, monohydrochloride] as an additional pharmacologically active substance.   17. Use according to any one of claims 1 to 16, wherein the medicament is combined with at least one additional pharmacologically active substance before and / or during and / or after treatment. Use applied to.   20. Use according to claim 19, wherein the medicament contains a GHS receptor antagonist and the additional pharmacologically active substance is an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, Use which is preferably rimonabant [1H-pyrazole-3-carboxamide, 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N-1-piperidinyl-, monohydrochloride]. The following compound 1 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 2 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 3 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 4 (R) -N- (1- (5-benzyl-4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 5 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 6 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 7 (R) -N- (1- (4- (3-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 8 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 9 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 10 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 11 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (naphthalen-1-ylmethyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 12 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 13 (R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 14 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (4-bromobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 15 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 16 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 17 (R) -N- (1- (4,5-bis (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- ( 1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 18 (S) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 19 (R) -N- (1- (4- (3-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 20 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 21 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3,5-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 22 (R) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 23 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 24 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5- (3- (1H-indol-3-yl) propyl) -4H-1, 2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 25 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2-methoxy) benzyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 26 (R) -N- (1- (4- (2-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 27 (R) -N- (2- (1H-indol-3-yl) -1- (4- (naphthalen-1-ylmethyl) -5-phenethyl-4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 28 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (3,4-dichlorobenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 29 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-fluorobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 30 (R) -N- (1- (4- (4-fluorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 31 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 32 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,
Compound 33 (R) -N- (1- (4- (4-methylbenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 34 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methylbenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 36 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-2-carboxamide,
Compound 37 (R) -N- (1- (4- (4-methylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 38 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminobenzamide,
Compound 39 (R) -N- (1- (5-benzyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 40 (2S, 4R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -4-hydroxypyrrolidine-2-carboxamide,
Compound 41 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,
Compound 42 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,
Compound 43 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 44 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) piperidine-4-carboxamide,
Compound 45 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 46 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 47 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 48 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,
Compound 49 (R) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,
Compound 50 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminoacetamide,
Compound 51 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-2-yl) acetamide,
Compound 52 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-4-yl) acetamide,
Compound 53 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) cyclohexanecarboxamide,
Compound 54 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 55 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,
Compound 56 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -3-aminopropanamide,
Compound 57 (S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-aminopropanamide,
Compound 58 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-3-yl) acetamide,
Compound 59 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -3- (pyridin-3-yl) propanamide,
Compound 60 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 61 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 62 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) piperidine-4-carboxamide,
Compound 63 (R) -N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) piperidine-2-carboxamide,
Compound 64 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) picolinamide,
Compound 65 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) isonicotinamide,
Compound 66 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) pyrazine-2-carboxamide,
Compound 67 (R) -N-1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3- Yl) ethyl) piperazine-2-carboxamide,
Compound 68 (S) -N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 69 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,
Compound 70 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2, 4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 71 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) pyrazine-2-carboxamide,
Compound 72 (R) -N-1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3 -Yl) -2- (1H-indol-3-yl) ethyl) piperazine-2-carboxamide,
Compound 73 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 74 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) ethanamine,
Compound 75 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-aminoacetamide,
Compound 76 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) pyrazine-2-carboxamide,
Compound 77 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) isonicotinamide,
Compound 78 (R) -N-1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) piperazine-2-carboxamide,
Compound 79 (R) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) picolinamide,
Compound 80 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 81 (R) -N-1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-Indol-3-yl) ethyl) piperazine-2-carboxamide,
Compound 82 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-2-yl) acetamide,
Compound 83 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) piperidine-4-carboxamide,
Compound 84 (R) -N-1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) Ethyl) piperazine-2-carboxamide,
Compound 85 (R) -N- (1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) pyrazine-2-carboxamide,
Compound 86 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-cis-aminocyclohexanecarboxamide,
Compound 87 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-3-carboxamide,
Compound 88 (R) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-2-carboxamide,
Compound 89 (S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 90 (R) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 91 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 92 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-bromobenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 93 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2-phenylethyl) -2-amino-2-methylpropanamide,
Compound 94 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (thiophen-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) piperidine-4-carboxamide,
Compound 95 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 96 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 97 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 98 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 99 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 100 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-methyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 101 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 102 (R) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 103 (R) -N- (1- (5- (3- (1H-indol-3-yl) propyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 104 (R) -N- (1- (5-((1H-indol-3-yl) methyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H -Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 105 (R) -N- (1- (5-benzyl-4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,
Compound 106 (R) -N- (1- (5-benzyl-4- (2,2-diphenylethyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 107 (R) -N- (1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,2-diphenylethyl) -4H-1,2,4-triazole- 3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 108 (R) -N- (1- (4- (3,5-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 109 (R) -N- (1- (4,5-dibenzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino -2-methylpropanamide,
Compound 110 (R) -N- (1- (5-benzyl-4-hexyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,
Compound 111 (R) -N- (1- (4- (2- (1H-indol-3-yl) ethyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 112 (S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 113 (R) -N- (1- (4- (3,5-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 114 (R) -N- (1- (4- (4-bromobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 115 (R) -N- (1- (4- (2-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 116 (S) -N- (1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 117 (R) -N- (1- (4,5-diphenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino -2-methylpropanamide,
Compound 118 (R) -N- (1- (4- (3,4-dichlorobenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 119 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) ethanamine,
Compound 120 (R) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2-phenylethyl) -2-amino- 2-methylpropanamide,
Compound 121 (R) -N- (1- (4- (4-fluorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 122 (R) -N- (1- (4- (3,4-dichlorobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 124 (R) -N- (1- (4- (4-methylbenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 125 (S) -N- (1- (4- (4-methoxybenzyl) -5- (3-phenylpropyl) -4H-1,2,4-triazol-3-yl) -2- (1H- Indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 126 (S) -N- (1- (4- (4-methoxybenzyl) -5-benzyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 128 N-((R) -1- (4- (4-nitrobenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 129 (S) -N- (1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 130 (R) -N- (1- (4- (4-methoxyphenethyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 131 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (thiophen-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 132 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 133 (R) -N- (2- (1H-indol-3-yl) -1- (5-phenethyl-4- (pyridin-2-ylmethyl) -4H-1,2,4-triazole-3- Yl) ethyl) piperidine-3-carboxamide,
Compound 134 (S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 135 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminoacetamide,
Compound 136 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-4-yl) acetamide,
Compound 137 (2R) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-2-carboxamide,
Compound 138 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) picolinamide,
Compound 139 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminopyridine-3-carboxamide;
Compound 140 (2S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-aminopropanamide,
Compound 141 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) isonicotinamide,
Compound 142 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) piperidine- 4-carboxamide,
Compound 143 (2S) -N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) Ethyl) pyrrolidine-2-carboxamide,
Compound 144 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) -2 -Aminoacetamide,
Compound 145 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) -2 -(Pyridin-2-yl) acetamide,
Compound 146 N-((R) -2- (1H-indol-3-yl) -1- (5-phenethyl-4-phenyl-4H-1,2,4-triazol-3-yl) ethyl) picolinamide ,
Compound 147 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 148 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 149 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,
Compound 150 (2S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-ethylphenyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) pyrrolidine-2-carboxamide,
Compound 152 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4-triazole-3- Yl) -2- (1H-indol-3-yl) ethyl) -2-aminoacetamide,
Compound 153 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-trans-aminocyclohexanecarboxamide,
Compound 154 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2- (pyridin-3-yl) acetamide,
Compound 155 (3S) -N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-3-carboxamide,
Compound 156 N-((R) -1- (4- (4-ethylbenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-aminobenzamide,
Compound 157 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) picolinamide,
Compound 158 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) piperidine-4-carboxamide,
Compound 159 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) picolinamide,
Compound 160 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3 -Yl) ethyl) -2- (pyridin-2-yl) acetamide,
Compound 161 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) pyrazine-2-carboxamide,
Compound 162 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) -2-aminoacetamide,
Compound 163 N-((R) -2- (1H-indol-3-yl) -1- (4- (2,4-dimethoxyphenyl) -5-phenethyl-4H-1,2,4-triazole-3) -Yl) ethyl) piperidine-4-carboxamide,
Compound 164 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) picolinamide,
Compound 165 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-acetamide,
Compound 166 N-((R) -1- (5-benzyl-4-((pyridin-2-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-4-carboxamide,
Compound 167 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 168 N-((R) -1- (5- (4-methoxybenzyl) -4-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -2-amino-2-methylpropanamide,
Compound 169 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) picolinamide,
Compound 170 N-((R) -1- (5-benzyl-4-((pyridin-4-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-acetamide,
Compound 171 (R) -benzyl-3- (2-aminoisobutyramide) -3- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1 , 2,4-triazol-3-yl) -propanoate,
Compound 172 N-((R) -1- (5-benzyl-4-((pyridin-3-yl) methyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indole -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 173 N-((R) -1- (4-benzyl-5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2 -Amino-2-methylpropanamide,
Compound 174 N-((R) -2- (1H-indol-3-yl) -1- (4-methyl-5-phenethyl-4H-1,2,4-triazol-3-yl) ethyl) picolinamide ,
Compound 175 N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4-phenyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 176 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) benzamide,
Compound 177 (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) -N-phenylmethanesulfonylamine,
Compound 178 (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) -N-tosyl ethanamine,
Compound 179 N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -2-amino-2-methylpropanamide,
Compound 180 N-1-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) ethane-1,2-diamine,
Compound 181 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 182 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) picolinamide,
Compound 183 N-((R) -1- (4-((furan-2-yl) methyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) piperidine-4-carboxamide,
Compound 184 N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ) Ethyl) -tetrahydro-2H-pyran-4-carboxamide;
Compound 185 N-((R) -1- (5-((1H-indol-3-yl) methyl) -4- (3-methoxybenzyl) -4H-1,2,4-triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2-amino-2-methylpropanamide,
Compound 186 (2S) -N-((R) -1- (4- (4-methoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole) -3-yl) ethyl) -2-amino-3-phenylpropanamide,
Compound 187 (R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (2,4-dimethoxybenzyl) -4H-1,2,4-triazol-3-yl ) -2- (1H-indol-3-yl) -N-tosylethanamine,
Compound 188 N-((R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole-3) -Yl) ethyl) -4-azidobenzamide,
Compound 189 N-benzyl- (R) -1- (4- (2,4-dimethoxybenzyl) -5-phenethyl-4H-1,2,4-triazol-3-yl) -2- (1H-indole- 3-yl) etanamin,
Compound 190 (2S) -N-((R) -1- (5- (2- (1H-indol-3-yl) ethyl) -4- (4-methoxybenzyl) -4H-1,2,4- Triazol-3-yl) -2- (1H-indol-3-yl) ethyl) -2,5-dihydro-1H-pyrrole-2-carboxamide,
A triazole compound selected from the group consisting of:   A pharmaceutical composition comprising a pharmacologically active amount of at least one compound according to claim 21.   23. The pharmaceutical composition according to claim 22, wherein the active ingredient is present in a unit dose of 0.001 mg to 100 mg per patient body weight.   24. A pharmaceutical composition according to any one of claims 22 to 23, wherein the composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. object.   25. A pharmaceutical composition according to any one of claims 22 to 24, wherein the composition comprises at least one further pharmacologically active substance.   26. The pharmaceutical composition according to claim 25, wherein the further pharmacologically active substance is an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, most preferably rimonabant [1H-pyrazole-3- Carboxamide, 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N-1-piperidinyl-, monohydrochloride].

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